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Copy of Lecture Expertise 2
Transcript of Copy of Lecture Expertise 2
* Made up of the following components:
- Nuclear envelope: encloses the nucleus and separates it from the cytoplasm which is made of a double membrane.
- Pore complex: pores regulate the entry and exit of proteins and RNA.
- Nuclear lamina: maintain the shape of the nucleus and support it
- Chromosomes: the organization of DNA!
-Nucleolus: contains rRNA This should be a review
of the last expertise Keep this in mind! It's very important later! Mitochondria The mitochondria Functions?
* Organelle in which cellular respiration occurs
* ATP (Adenosine triphosphate) is generated Components?
*Enclosed by two phospholipid bilayers
-Outer membrane is smooth
-Inner membrane is Complex
* Intermembrane space - area between the inner and outer membranes
* Mitochondrial Matrix- enclosed by the inner membrane, contains enzymes, mtDNA, and ribosomes. Mitochondria (in depth) * Mitochondria create energy by using carbohydrates (sugar molecules such as glucose) and fatty acids to break down when in the presence of Oxygen. The energy inside the organic molecules are used to create ATP during the following processes of cellular respiration: glycolysis, oxidation of pyruvate, krebs cycle, and through the Electron transport chain. Equation:
Glucose (C6H12O2) + Oxygen (O2) ATP (energy) + 6 H20 + 6CO2 What the hell does that even mean? Maybe this will help... Glucose loses an electron and Carbon dioxide gained one. Glucose is nice enough to act as an electron carrier and hands over its hydrogens. These hydrogens attach to the Oxygen and creates H20. This still doesn't make sense too me... Well, we haven't exactly covered this part in class yet. So just keep the equation in mind and remember that it's because of mitochondria! What about the other stuff? Ah...that's a bit more of a challenge. No. Glycolysis: process in which glucose is broken down This part is actually pretty awful. So... I'll just tell you the end products. It will be easy as... Glycolysis:
-converts 6-carbon glucose into two 3-carbon pyruvates.
- Produces 4 ATP and 2 NADH
-Consumes 2 ATP
- Net yield= 2 ATP and 2 NADH. Oxidation of Pyruvate
-3 carbon glucose is stripped off to be oxidized. This drops a CO2.
- If O2 is available, pyruvate enters the mitochondria
1) 2 CO2 are released
2) 2 NAD are reduced to 2 NADH
3) Produced Acetyl CoA 1 2 Krebs Cycle
- 2-carbon Acetyl CoA enters mitochondrial matrix
- 2 carbon Acetyl CoA binds with 4 C OAA
- 6 carbon citrate created
- Citrate lose 2 carbons and forms a 4 carbon molecule
- NAD+ changes into 2 NADH
-ATP is created
-FADH2 is created an acts as another electron carrier
Net gain: 2 ATP, 8 NADH, 2 FADH2 3 4 ETC
-made up of a series of proteins that are built into the inner mitochondrial membrane (along the cristae)
- Contains transport proteins and enzymes
-Transporting electrons linked to creating a hydrogen gradient
-Yields roughly 36 ATP from 1 glucose molecule; oxygen is necessary (remember, the important products of the other steps are the electron carriers)
-Hydrogen from NADH creates a proton gradient and causes protons to flow through the ATP synthase (high to low concentrations) Electron Transport Chain and Chemiosmosis Will it be fun? Was there any particular reason that I just went through that hell? This is about ORGANELLES. Not torture (also known as cellular respiration). Yes. All of those processes occur near/in the mitochondria. Remember? Mitochondria = ATP? I don't understand how ALL that could happen in a baby sized mitochondria. I thought you might say that... Notice how it all ties in together? the mitochondria matrix? The phospholipid bilayer? The integral proteins? the intermembrane space? It all connects together. You went through all that information just to show me some crappy drawing? Regardless, the cellular respiration is just a broader picture of all the functions an individual organelle goes through. Plus, you never know when you might have a need for obscure information that you've long since forgotten. A little quick brush up on the process might help at a later date for another exam. For now, focus on knowing that it's really important and takes place in the mitochondria. Peroxisomes Peroxisome Function:
-capable of converting hydrogen peroxide into water or a compound that is less toxic to cells.
-breaks down many other substances (uric acid, amino acids, fatty acids)
-important with lipid synthesis and bile acids in liver Why do peroxisomes even matter? Aside from the above functions, mutations in peroxisomes can cause severe disorders such as Zellweger Syndrome. This syndrome is caused by an autosomal (lethal) recessive allele that stops the proper formation of the peroxisomes. Unfortunately, the liver, brain, and kidneys are severely affected. Many of the problems that affect the brain are caused by a destruction of the myelin (forms the myelin sheath which insulates the axon for faster signaling) basically, mutated peroxisomes can cause problems with neural impulses. Neural impulses and the myelin sheath with be discussed in greater detail later. However, it is important to show how interrelated the components of the cell are. Organelles can directly influence/hinder many of the bodies biological processes. The Lysosome As shown in the video, Lysosomes have a very specific function:
- They are a digestive organelle which have the ability to 'digest' macromolecules by hydrolysis.
- Lysosomes have very high pH's which allow them to easily remove unneeded components from the cell. The video also showed the process of exocytosis and endocytosis. In the case of the lysosome, the unneeded cellular component was 'engulfed' by the cell, digested, then 'kicked out'. What do you mean by 'engulfed' and 'kicked out'? Don't worry, we'll get there next. But first we have to look into a very important and serious issue many people face. Imagine that this...uh...alien thing is a cell. I don't think I have that great of an imagination. The cell then encounters some cellular component, maybe it's a food particle, a viruses, or a bacteria. Who knows? But that delicious green burger is what the cell wants to bring into it's cytoplasm. Alien cell baby. delicious burger aka "cellular component" So we've established that the cell wants it, how does it actually get inside? The cell ("alien cell baby") extends it's plasma membrane (terrifying mouth) around the cellular component (delicious green burger). A vesicle is formed around the cellular component once it has been enclosed by the plasma membrane. Finally, the cellular component is within the cell. (Alien cell baby's hunger for a deliciously green burger has been quenched). Happy alien baby. Where do the lysosomes come in? At this point, the lysosomes in the cell will merge with the phagosome (the vesicle containing the cellular component.) After the merging, the structure is called a phagolysosome. The phagolysosome will then use it's acidic environment to break down the component. Since the cell doesn't want to keep the debris inside the cytoplasm all day, it is released via exocytosis. I kind of see how endocytosis connects with lysosomes...I'm going to regret this. But what exactly IS exocytosis? I'm so glad you asked! Let me "paint you a picture"! Please stop. Just...no. Oh god, I do not want to see a terrible image of this thing throwing up. Of course not! But 'throwing up' is a good way to think of exocytosis. Similar to the body's response to remove until wanted contents by pushing it out of the body, our cells do the same thing! Gross. We start now, after the phagolysosome has completed it's function of digesting via hydrolysis, the contents of the vesicle. Now, however, a lot of debris is left behind. Cellular debris in vesicle Imagine that the contents of the vesicle holds trash, like empty drink bottles, crumpled papers, used bandaids and tissues. Obviously, it's nothing that you want to hold onto. However, in some cases (like with organelle digestion) many of the components can be 'recycled' (absorbed) much in the same way that our plastic bottles and papers can. However, much like with traditional recycling, not everything can be reused (aka used bandaids) Therefore, the cell must get rid of this. In order to push the contents out of the cell, the vesicle must first make it's way to the plasma membrane. Cellular debris moves close to plasma membrane The vesicle containing the cellular debris fuses with the plasma membrane. Which creates an opening where the debris are capable of leaving the cell. The vesicle then empties the cellular debris from the cell. Leaving the vesicle empty of all the 'trash'. Finally, the cell ("Alien cell baby") can now return to its normal (creepy) state. And it's free to continue the process of endocytosis, lysosome digestion, and exocytosis. The process of endocytosis and exocytosis are important for other processes such glucose transport, transporting vesicles around the cell, along with many other functions. The Endosome Endosomes Function:
-After endocytosis occurs and the components are within the cell, the endosomes are the vesicles that transport the contents. Types:
1) Early Endosomes
2) Late endosomes Locations:
Near periphery of cell
Close to the nucleus Early Endosome
-sorts out the cellular components brought in by endocytosis. These contents can contain ligands which have specific functions and need to be directed to the proper area. Late Endosomes
-vesicles carrying lysosomal enzymes from the trans-golgi complex fuse with the late endosomes and form Lysosomes. Autophagosomes Autophagosomes Autophagy:
- process that occurs when a damaged organelle becomes surrounded by a double membrane, lysosome fuses with the outer membrane of this vesicle and the enzymes break down the material inside. The components are then released through exocytosis. But what is an autophagosome? Autophagosome: the name of the structure when a organelle (or other cellular component) is surrounded by the double membrane. Autophagolysosome: the name of the structure when the lysosome fuses with the double membrane and degradation occurs. Seems a lot like a lysosome... Actually, the autophagosome uses a lysosome and becomes an autophagolysosome. Who came up with these names? Someone who clearly hates students. Cytoskeleton Cytoskeleton Three types of structures are used to create the cytoskeleton: 1) Microtubules: -made of Tubulin
* Maintain cell shape
* Cell motility
* Have functions with chromosome movement during cell division
* organelle movement What is tubulin? Tubulin are globular proteins that come together to form the microtubules. 2) Microfilaments: -made of actin
*maintains and changes cell shape
*role in muscle contraction
*cell division What's actin? Actin is another globular protein that forms the microfilaments 3) Intermediate Filaments: -contains proteins within the Keratin family but can also contain others depending on the cell type.
*Maintains cell shape
*Anchors nucleus and other organelles
* Forms the nuclear lamina Ribosomes Ribosomes We learned a lot about ribosomes in the last expertise. However, it's important to make two distinctions between ribosomes when looking at the Endoplasmic reticulum and Golgi Apparatus. Bound Ribosomes:
-attached to the RER (Rough Endoplasmic reticulum)
-These are used for protein synthesis (translation)
-For example: secreted proteins, integral membrane proteins, soluble proteins of organelles
-these a ribosomes that are allowed to float freely in the cells.
-For example: cytosolic proteins, nuclear proteins, peripheral membrane proteins, proteins that will be used with other organelles. Endoplasmic Reticulum Smooth Rough Smooth ER Functions:
- Synthesis of steroid hormones in endocrine cells
- Aids in detoxification of the liver with organic compounds
- In muscle cells, helps sequester Ca+ ions Why is that necessary? Calcium can interfere with reactions, since muscle cells rely on Calcium ions, sequestering them for a controlled released is a very important adaptation. Remember the double membrane of the Nucleus mentioned earlier? The nuclear envelope of the Nucleus is attached to the Smooth Endoplasmic reticulum. This allows the nucleus to directly deliver RNA needed to be assembled into protein.
-Especially rRNA since many are continuously needed to create ribosomes. Rough Endoplasmic Reticulum -Located further from the nucleus
-RER's polarity affects the flow of protein synthesis to protein discharge.
-Starts the biosynthetic pathway
-synthesis of proteins using bound ribosomes Endocytosis: There are three types of endocytosis:
1) "Bulk-phase endocytosis" - this is the uptake of fluids along with any molecules that come with it (pinocytosis) **Binding does NOT need to occur**
2) Phagocytosis - the uptake of food particles into a cell
3) Receptor-mediated endocytosis - binding of a ligand to a receptor causes it's uptake into a cell The Endocytic Pathway divided into two stages: Early and late endosomes So overall, what is the endocytic pathway? The Endocytic pathway is a process for moving materials from outisde the cell into endosomes and lysosomes on the interior so they can be sorted, moved, or destroyed. Phagocytosis cellular uptake of material (can occur with organelles, food particles, liquids and molecules, or bacteria/viruses) For a not awful picture of Endo- and exocytosis play this video!
Exocytosis starts at 9:20 (Don't worry, the video will be posted again later, for now, just watch the exo/endocytosis portion. Or watch the whole thing. It's your computer.) Phagosome What about the other types of endocytosis? The Pinocytosis and the receptor-mediated? I'm glad that you 'drew' that conclusion, those are coming up next. Wow, so corny. The Cell (shown here as a giant whale or fish) The mouth represents the intercellular portion of the cell while the area outside represents the extracellular. During pinocytosis, fluid as well as other molecules are taken into the cell. The other fish represent the various molecules that are pulled into the intercellular side. molecules (baby fish) Cell (Whale or fish) The process of pinocytosis is complete when the fluid and various molecules from the extracellular side are brought into the cell. Receptor-mediated Endocytosis is a little more complicated... This figure represents the ligand. (Seen here as a very fancy fat man with a hat) Plasma membrane is represented by the orange and black bar The dashed lines represent phospholipids embedded in the membrane The blue chairs are receptors within the "coated pit" area of the plasma membrane. Picture: The (fancy) fat man sits in the chair
In the cell: The ligand binds to the receptor. The "coated pit" is covered with Clathrin which causes the dip to form in the plasma membrane that begins to form the vesicle. Sadly, the fat man is terrified of the floor swallowing him whole. But in the cell, the ligand is fine with it. Clathrin:
forms the 'coat' of the coated pit. Clathrin is a protein that is forms that is extremely important in endocytotic direction. Once the vesicle completely closes, Dynamin is needed to fully remove the budding vesicle from the the plasma membrane. Dynamin:
A GTP-binding protein that forms a 'collar' around the area still attached the membrane. Hydrolysis of the GTP allows the vesicle to be securely removed. Triskelion:
A structure of the Clathrin which causes the membrane for fold from flat into a "cage" that surrounds the vesicle The ligand is almost within the cell at this point. Sadly, the fat man is probably realizing his certain doom. Luckily for the ligand, everything is fine. Not so much for the man. The dynamin protein completed it's hydrolysis and removed the vesicle from the plasma membrane. The vesicle (with the ligand inside) is now free to fuse with an endosome and be sorted. Plasma membrane returns to normal, ready to accept another ligand and start endocytosis again. The fat man is probably dead you know. No doubt. But! The ligand is free to create many new cellular processes and enter the endocytic pathway! Endocytic pathway? Endosomes? Organelles are getting pretty complicated. Don't worry, you'll learn about endosomes next. Hang on a bit, things will be clear soon. Since this process is "receptor-mediated" the ligand must travel to the plasma membrane and bind to the proper receptor (that is compatible with it) in order to enter the cell. Step One: Step Two: Lysosomal storage disorders, this video provides a quick overview but focuses on the 'human' aspect and is more simplified, but it helps to see the importance of lysosomes in the cell and how mutations can cause devastating effects.After this video, we'll explore the example of Tay-sachs with Lysosomal storage disorders. Click to the next slide for a full view of the video. Tay-Sachs Genetic aspect:
- Caused by a defect within chromosome 15 Cellular aspect:
-the defect prevents the production of hexosaminidase A
- when this happens, the gangliosides accumulate in the cell and the ganglion cells swell due to the inability to break down the gangliosides. remember: DNA to mRNA to Protein. If the DNA is incorrect from the start, the protein will not be properly made or is this case, it won't be made at all. Physiological aspect:
-When the gangliosides accumulate and cause swelling, it directly affects the function of the neurons. Medical aspect:
-various symptoms are caused by Tay-Sachs including (but not limited to): deafness, dementia, seizures, blindness, and loss of motor skills.
-The only treatments are to help support and comfort.
-Life expectancy: Possibly by 5 years, diseases worsens with time. Hexosaminidase A:
-lysosome that hydrolyzes gangliosides
-a lipid that aids in signal transduction and can be found mostly in the nervous system. The Rough Endoplasmic reticulum (RER) is a very important component of the Endomembrane System.
-series of organelles that work together that exist inbetween the nucleus and the plasma membrane.
etc. The RER is very important and plays a large role in answering the following questions: 1) What are the steps in transporting vesicles? 2) How are membrane-bound ribosomes synthesized? 3) How are proteins processed in the ER? 4)How are integral proteins synthesized? 5) How are membranes are synthesized via the ER? 6) How are membranes capable of different functionalities? I can't lie..this seems insanely tedious. I'm kind of over organelles. No kidding.. What? Nothing! Let's continue. 1) What are the steps in transporting vesicles? 1) The ER contains the components in it's lumen, the area within the lumen (with the components) swells, capturing the components. 2) This contains both the cellular components and the lumenal environment necessary for its stability. 3) The encapsuled components are pinched off and form a "free-floating" vesicle that travels through the cytoplasm (via exocytosis) 4) At this point "tagging" occurs which provides the vesicle with a marker that designates where it supposed to go. 5) Vesicle attaches to the extracellular side of the cell or of the organelle (via endocytosis) 6) Vesicles can bud from the RER and head toward the cis golgi through two pathways options at the golgi: Option #1
Vesicles sent to plasma membrane and excreted via exocytosis. Option #2
Vesicle is secreted but it contains a transmembrane protein which is delivered to the plasma membrane via exocytosis Read this Watch this OR cis golgi = close to the ER (accepts)
trans golgi = away from the ER (transports) 2) How are membrane-bound ribosomes synthesized? 1) mRNA binds to a free ribosome in the cytosol 2) Secretory proteins have a signal sequence that an SRP recognizes. SRP attaches to the SRP receptor. *Signal sequence is located on the N-terminal end of the polypeptide *SRP= Signal recognition particle Watch this OR Read this 3) The free ribosome attaches/binds to a translocon. *Translocon= protein-lined channel 4) SRP is released from the SRP receptor because of the presence of GTP-binding proteins 5) Signal peptidase cleaves the signal that binds to the SRP Why?
-This prevents the protein from rebinding and clogging up the pores 6) A chaperone can appear in the ER's lumen and help guide the protein as it is translated. 3) How are proteins processed in the ER? There are two main ways to process proteins: 1) Carbohydrate additions 2) Disulfide bond additions How? Oligosaccharltransferases:
- adds carbs to the proteins by inserting them into the intercellular side of the membrane
-the carbs are then flipped to the extracellular side of the cell How? -Chaperones aid in folding which contain protein disulfide isomerase enzymes
-These enzymes are capable of adding disulfide bonds to cysteines. 4)How are integral proteins synthesized? Background information:
*Integral proteins- contains a hydrophobic transmembrane area that alters how it can move into the RER lumen
*Translocon- a protein-lined channel that helps to orient the transmembrane sequence Two pathways: Option #1-
Orientation: N-terminus on the internal side of the membrane/ C-terminus external side *As the integral membrane is being synthesized, the hydrophobic region is recognized by the translocon
*The protein is released into the membrane because it's already in the proper orientation needed Option #2-
Orientation: N-terminus on the EXternal side/ C-terminus on the INternal side. *In this case, the protein needs to be switched by the translocon.
*The translocon flips the protein as the protein is being translated and allows the hydrophobic region to remain in the middle.
*As the integral protein is being delivered it's orientation is maintained Skip to the second half of this video in order to see the visual of this process again: 5) How are membranes are synthesized via the ER? 3 rules of membrane synthesis:
1) Membranes arise from pre-existing membranes
2) Lipids are inserted into existing membranes
3) Proteins and Lipids are modified based on its environment What happens? * New Phospholipids are inserted into the intercellular side of the membrane
*If a phospholipid has a flippase it has can "flip" to the opposite side of the membrane (extracellular side)
* Lipids can also be modified once they are embedded into the membrane But, how come some phospholipids have different functionalities? Inserting different types of phospholipids into the bilayer allow different side chains/groups which can cause different interactions within the cell and therefore, create variable functions. The Golgi Complex Golgi Complex Structure:
-made of flattened cisternae Remember cis vs trans golgi?
*cis golgi= towards the ER (accepts components)
*trans golgi= away from the ER (transports components) Functions: Cis golgi- sorts proteins from the ER that enter the golgi Trans golgi- sorts proteins into the membrane or other destinations Conflicting theories of Golgi Transport: 1) Cisternal Maturation model
2) Vesicular transport model Lastly, we'll being to discuss the intricacies of cell signaling! Is there anyway this will go quickly and painlessly? Depends on how much you've already studied... But as always, let's start slow... Cell Signaling:
The ability for cells to communicate with one another and respond to various stimuli. Cells contain Extracellular messenger molecules that are capable of stimulating cells at short or long distances within the body.
Other necessary components (include but are not limited too):
Receptors, various proteins, and enzymes Three Types of Intercellular Signaling 1) Autocrine signaling
2) Paracrine signaling
3) Endocrine signaling Autocrine Signaling "Real world" Example: "Cell world" -The source of the message and the target of the message is the same cell.
- The receptors to receive the message are located on the same cell that gives the message Self Cleaning Bathroom sprays
*The cleaner is located in the bathroom (cell) and ejects a solution (secreted molecule).
*However, the cleaner is being used to clean the same location (itself) Basically:
The secreted molecule binds to itself Paracrine Signaling "Cell world" "Real world" Example -the secreted molecule travels to nearby cells and those cells receive the message.
-They can only travel short distances because the molecules are unstable, easily degraded, or bind to the extracellular matrix Whispering a secret to your friend:
-You wouldn't share the secret with the world (the secreted molecule is only shared with those 'close to it')
-You wouldn't shout your secret across a crowded room, instead your "voice" (secreted molecule message) will only travel a short distance from your mouth to your friend's ear. Basically, the secreted molecules are shared with close cellular neighbors. Endocrine Signaling -Capable of traveling long distances via the bloodstream
- messages in the form of hormones General details about intercellular signaling:
*Remember- only cells with the proper messenger receptors can recognize and bind to the secreted molecules! Basics of Cell Signaling: Each of the signals sent by cells begin the similar ways and then split into various pathways. 1) Initial cell releases a messenger molecule that follows one of the following: Autocrine, paracrine, or endocrine signaling
2) If the target cell has the proper receptor the ligand (secreted molecule) is able to bind to the target cell.
3) Signal passes through to the inner portion of the plasma membrane. Two possible routes can be taken at this point: 1) Effector pathway
2) Non-effector pathway Effector pathway The signal (caused by the ligand binding) leads to an Effector generating a second messenger.
The second messenger is used to recruit the necessary proteins needed to perform the functions dictated by the original signal Let's start with the effector path Effector= enzyme that brings a second messenger
Second messenger= small substance that can activate/inactivate specific proteins Non-effector Pathway In this pathway, once the ligand binds the receptor itself is capable of recruiting the necessary protens without the aid of additional molecules. Regardless of the pathway... -Once a receptor is activated and it's pathway is chosen, a conformational change occurs (via protein kinase and phosphorylation)
-this conformational change will eventually lead to a signal being carried out by the cell. Possible signals:
-Movement With the basics of cell signaling out of the way, there are two more definitions/concepts we need to learn before getting into the "meat and potatoes" Function:
transfer phosphate groups to serine and threonine residues of their protein substrates Protein Kinases Function:
activate/deactivates enzymes, increase/decrease protein interactions, signal protein degradation Phosphorylation Both of these definitions will play a large roles in the in depth portions of cell signaling pathways, be sure to be pretty familiar with these terms. What is Signal Transduction? (it's a video so click it) - a (detailed) process that carries info via extracellular messenger molecules and causes changes within the cell(s). As we've previously seen, there are many different types of receptors, but since it's been awhile, let's make sure you remember the details about GPCRs and G-proteins. What is one of the most characteristic features of a GPCR? It contains 7 transmembrane helices What is the function of the helices? allows a particular structure to form and transmit signals Which portion of the GPCR interacts with G proteins? The intracellular side Good! (Or maybe bad depending on how you answered those questions, if you need more review, check the receptor section again!)
Next, a quick review on G-proteins! What is the (general) function of a G-protein? Okay! With that background covered again, you should be pretty clear with cell signaling right? -It acts a the 'trigger' for intracellular messages What are the important structural components of an inactivated G-protein? G-alpha, G-beta, G-gamma, GDP and it also contains tethers that aid in anchoring close to the receptor. What are the important structural components of an activated G-protein? G-alpha and GTP How can a mutation in the tethers affect signal transduction? Without the tethers, the G-protein may 'wander' off and be too far away from the receptor to receive the signal and become activated. This would prevent the rest of signal transduction from occurring. What does it mean for the G-protein to be "heterotrimeric"? It contains 3 different subunits (alpha, beta, and gamma) How is GPCR stabilized? By noncovalent interactions uh... Don't worry, there will be plenty of examples to help put this in perspective! A few more questions.... Signal Transduction with GPCRs I know what you're thinking. "What the hell happens during all this? It seems crazy complicated." You need reassurance that the night before the exam, you have a chance in hell of passing. Well...sorry, it is complicated. But! once you break it down, it's much better. The Steps: Binding and Conformational changes 1) A ligand attaches to the GPCR on the extracellular side of the cell Here 2) The ligand causes the noncovalent interactions to shift and causes a conformational change. 3) The conformational change increases the desire for a G-protein to attach to the GPCR (and it does) 4) After the G-protein attaches, a third conformational change occurs. GDP dropped GTP gained 5) Since, GTP is attached, the G-alpha 'dislikes' G-beta and G-gamma. At this point they are removed. What pathway do GPCRs use? The effector pathway The effector pathway The example: Binding and conformational changes The ligand binding to the GPCR is simple, therefore, that should be the easiest part to remember. Additionally, the addition of the G-protein to the receptor is also pretty straight forward. However, how do you keep track of the conformational changes? With this example, imagine the components represent the following:
GPCR binding = potential relationship
GDP = Common Sense
G-protein subunits (Beta and gamma) = Best friends of G-alpha
GTP = New boyfriend/girlfriend G-protein attaches to GPCR, leads to conformational change GDP leaves and GTP arrives G-beta and G-gamma leave because they are 'disliked' by the new G-alpha and GTP complex The Steps: Effector Pathway and 2nd messenger Potential relationship causes a change Common sense leaves as a new boyfriend/girlfriend enters their life Old friends and new boyfriend/girlfriend do not get along and the friends are 'cut out' of the life of the new couple 6) The G-alpha and GTP complex activate the necessary effector protein 7) Effector activation leads to the production of the second messenger (in many cases, cAMP) Second messenger:
activate multiple cellular signaling proteins 8) After the second messenger is produced, the G-alpha hydrolyzes the GTP. GTP GDP + inorganic phosphate 9) Heterotrimeric G-protein is reformed (G-alpha, G-gamma, G-beta) The Steps: Termination 1) GPCR is phosphorylated by a GRK (G-protein coupled receptor kinase)
2) Phosphorylation of GPCR allows Arrestins to bind Why is it necessary to terminate the signal at the GPCR? This will prevent overstimulation and the cell will regain it's sensitivity to the signal. The signal must be stopped at the GPCR because the G-protein's sequence of events is triggered by it's binding to the GPCR. What are Arrestins and how do they function? Arrestins are proteins that compete with G-proteins for binding sites on the GPCR. Arrestins prevent the signal from being continued because it blocks up the binding sites of the GPCR. FUN FACT!
-Cholera causes death via dehydration
-The Cholera toxin prevents termination of adenyl cyclase molecule (effector) and causes it remain active. This leads to continuous fluid being removed from the intestinal lumen. Second messengers We just went through an example of how a second messenger affects the cell with cAMP, generally, cAMP is used to stimulate glucose mobilization by activating a protein kinase However, there are many other second messengers. Phosphatidylinositol 2nd messengers:
Phospholipids are useful for more than just structural support for the cell. Certain types of phospholipids are used to send messages as well. 1) Diacylglyerol (DAG)- activates effectors like protein kinase C 2) PKC (Protein Kinase C)- important with growth 3) Inositol 1,4,5- triphosphate (IP3)- contains a sugar phosphate causes Calcium channels to open This will be explored more later. Signal Transduction of Protein-tyrosine phosphorylation Remember, awhile ago when we discussed protein kinases? Now, we're using protein-tyrosine kinases, what does that mean? The music is terrible, but the animation is cool. Feel free to mute the video. Protein-tyrosine kinases phosphorylate specific tyrosine residue on proteins. There are two types of signal transduction for protein-tyrosine phosphorylation:
1) Receptor protein tyrosine kinases (RTKs)
2) Cytoplasmic protein-tyrosine kinases These are basically as simple as they sound:
-RTKs contain a integral membrane protein while Cytoplasmic protein-tyrosine kinases do not have a receptor involved. Mechanism for RTKs One in the first steps of RTKs is Receptor Dimerization There are two pathways that RTKs can take to complete this step:
1) Ligand-mediated dimerization
2) Receptor-mediated dimerization Let's start with ligand-mediated Ligand-mediated dimerization Example:
-Think of the monomers as wheels of a bike. They are both separate but exist in an "inactive" form.
-The ligand is the bike frame which contains the linkage for BOTH of the bike wheels.
-the metal part/"ligand" binds to the wheels "monomer" and creates an active bike. Important characteristic: The ligand that connects both monomers at the same time. *The receptors are two separate monomers and the ligand is made of two "halves" that bind to the separate monomers and pull them together to form a dimer. Two separate monomers Bike wheels Ligand with two spots for binding Bike frame Dimerization occurs Active dimer "functional" bike Receptor-mediated dimerization -Two ligands attach to the monomers separately
-The binding of the ligand to each monomer causes a conformation change
-The change allows the two monomers to interact and bind together to form an active dimer. Important characteristic: The ligands that attach to the monomer are separate. Mechanism of RTKs 1) Receptor Dimerization
2) Trans-autophosphorylation What is trans-autophosphorylation? -process where each monomer phosphorylates the other.
-this opens up binding sites for other signaling molecules Example: Spreading of germs when making out Person A Monomer A Monomer B Monomer B Phosphorylates Phosphorylates Monomer A Person A Person B Person B gives their
germs to gives their
germs to The word looks awful, but it's actually a pretty easy definition. Mechanism of RTKs When are RTKs activated?
-when signaling proteins with the proper domain bind to the autophosphorylated sites 1) Receptor Dimerization
3) Activation of other signal pathways Ligand-mediated Receptor-mediated Trans-autophosphorylation What are the four types of signaling protein? 1) Adaptor proteins
2) Docking proteins
3) Transcription Factors
4) Signaling enzymes Adaptor proteins Function:
-brings additional proteins to the RTK to form a complex Docking Proteins Function:
- The receptor phosphorylates the docking proteins
-The phosphorylated sites can bring in new signaling molecules
-The new sites open the possibility for versality because various docking proteins can turn on various signaling molecules. Transcription Factors Function:
-A STAT molecule with the proper domain and binding site attaches to another STAT molecule
- The 2 STAT molecules form a dimer and travel to the nucleus
-stimulate transcription Signaling Enzymes Activation
-Three possible routes of activation:
1) Translocation to the membrane
2) Binding leads to a conformational change and new enzyme activity
3) Phosphorylation All three result in biochemical changes within the cell What is active transport and what type of energy drives it?
Active transport: The energy requiring process in which a substance binds to a specific trans-membrane protein, changing its conformation to allow passage of the substance through the membrane against the electrochemical gradient for that substance. Question 6: Active Transport The GLUT 4 Glucose Transporter Voltage-gated K+ Ion Channel Voltage-gated potassium channels are trans-membrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state. Voltage-gated Ion Channels Step by Step… Active Transport, and the Sodium/Potassium pump Like facilitated diffusion, active transport depends on integral membrane proteins that selectively bind a particular solute and move it across the membrane in a process driven by changes in the protein’s conformation.
Unlike facilitated diffusion, however, movement against the concentration gradient requires the coupled input of energy.
*Refer back to Biology Crash Course video to recall the vending machine analogy of active transport* Active Transport These transporters are integral proteins and they work by binding to the substances that need to travel through
Transport proteins help glucose and amino acids travel through the membrane
Transport proteins are specific for the molecules they transport.
Lets look at a Glucose Transporter in Action… Facilitated Transport Larger molecules need to get through the membrane but can’t on their own…they need a transporter So, lets break it down… Are there substances what cannot utilize ion channels and cannot diffuse straight through the membrane?
Yes! That’s where facilitated diffusion kicks in…but before we discuss this, lets cover a few more definitions! Question 5: Facilitated Diffusion Different ion channels have different sensors that enable them to detect different conditions and hence they are classified depending on their sensing mechanisms.
Some of them respond to changes in the membrane potential; these are known as voltage-gated ion channels.
Others respond to small chemicals (ligands) that bind to specific sites within the protein; these are termed ligand-gated ion channels.
The channels that respond to deformations or stretching of the membrane such as when you tread on a pin or listen to music are called mechano-gated. Ion Channels Why are ion channels needed, what kinds of substances travel through them, and what kind of ion channels are there?
Not only does size play a role in how a substance travels through the lipid bilayer of the membrane, but polarity also makes a difference. Ions like NA+, K+, Ca2+, and Cl- are extremely important to cellular activity but their charge does not allow them to diffuse through the membrane without assistance. Luckily there are ion channels that allow them to travel through. Question 4: Transport through Ion Channels
What kind of substances can diffuse right through the membrane?
Small, inorganic molecules, such as Oxygen, Carbon dioxide, and Nitrogen oxide are able to diffuse straight through the membrane. This is helpful to the cell because, in the case of Oxygen, the cell readily is in need of the molecule and depends on it for survival. Question 3: Simple Diffusion
How do substances diffuse through the membrane?
Substances travel through the membrane passively (by diffusing through and traveling down the concentration gradient) in three ways. They can either:
1. Diffuse straight through the lipid bilayer
2. Rely on protein lined ion channels
3. Get help diffusing through from a protein transporter Question 2: Passive Transport Diffusion: a type of passive movement of molecules, or particles along a concentration gradient, or from regions of higher to regions of lower concentration
Concentration gradient: the result of an unequal distribution of ions across the membrane of a cell that allows for the movement of solutes. Vocabulary Intermission How do substances move through a membrane?
Substances move through the membrane of cells in two ways:
1. Passively (by means of Diffusion)
2. Actively (with the help of a protein pump
Before we dive into the mechanics of Passive Transport, lets
review a few definitions… Question 1
To figure out how membrane transport works, we will be answering a series of questions Membrane Transport Questions Heather Dover Membrane Transport Step by Step… Active Transport, and the Sodium/Potassium pump Step by Step… Active Transport, and the Sodium/Potassium pump Step by Step… Active Transport, and the Sodium/Potassium pump
You’re welcome though Ok, ok….not that Transporter http://www.tumblr.com/tagged/transporter%203 The Transporter http://biology.about.com/od/cellularprocesses/ss/diffusion_2.htm Facilitated diffusion: transport of substances across a membrane from an area of higher concentration to an area of lower concentration by means of a carrier molecule (aka a facilitative transporter).
Facilitative transporter: a trans-membrane protein that binds a specific substance, and in doing so, changes conformation so as to facilitate diffusion down the concentration gradient. Vocabulary Intermission http://www.thenakedscientists.com/HTML/features/article/the-ion-channel-through-the-keyhole/ A number of human diseases are directly caused by ion channels that fail to function correctly. In some cases these are the result of mutations or changes to the genes that encode the ion channel proteins themselves. Cystic fibrosis, epilepsy and certain heart rhythm problems (arrhythmias) like "long QT" syndrome are examples of this phenomenon.
It's not all down to genetics though because some food-poisoning bacteria have evolved to exploit our ion-channel vulnerability to good effect through the production of toxins that can trigger diarrhea by interacting with ion channels in the cells lining the intestine. Health Issues http://www.thenakedscientists.com/HTML/features/article/the-ion-channel-through-the-keyhole/ Ion channels are highly selective in allowing only one particular type of ion to pass through.
Ion channels rely on concentration gradients for ion transport. Ion Channels Thinking back on Chapter 4, and the functions of the plasma membrane of cells, remember:
The plasma membrane can be compared to a moat around a castle: both serve as a general barrier, yet both have gated “bridges” that promote the movement of select elements into and out of the enclosed cell.
The membrane’s transport machinery allows a cell to accumulate substances, such as sugars and amino acids, that are necessary to fuel its metabolism and build macromolecules.
*in a nutshell, the membrane must protect the cell; keeping cytosol and intracellular substances from leaking out and only allowing necessary substances into the cell.* Transport through the Plasma Membrane Moving on to the next type of Transport, Active Transport, and the last question Passive transport is a kind of membrane transport by which ions and molecules move along a concentration gradient. There are three ways in which passive transport can occur:
1. Simple diffusion through the membrane
2. Gated Ion Channels
3. With the help of transporter proteins embedded in the membrane. To Recap… http://www.shutterstock.com/pic-46393198/stock-vector-simple-diffusion-through-a-plasma-membrane.html Remember…
In order for simple diffusion to take place, there must be a higher concentration of substance on one side of the cell as compared to the concentration of that substance on the inside of the cell. Diffusion always follows the concentration gradient. ALWAYS! ATP- powered pumps couple the energy released from the hydrolysis of ATP with the transport of substances across the cytoplasmic membrane. ATP- powered pumps are used to transport ions such as Na+, Ca2+, K+, and H+ across membranes against their concentration gradient. ATP supplies the energy needed for a protein pump to work against the concentration gradient. For this reason, action transport drives the movement of ions in only one direction. In other words, the pump only needs “power” from ATP when transporting from the inside to the outside of the membrane. Active Transport As you can see the plasma membrane is a highly dynamic structure were varies cellular functions occur… For proper cellular function to take place the membrane needs to maintain its fluid nature
Temperature can drastically affect the fluidity of the membrane, known as the transition temperature
The level of unsaturation increases as the temperature drops and prevents membrane rigidity
The fluidity of the plasma membrane is the perfect compromise between rigid ordered structure with no movement and a completely liquid structure in which orientation and mechanical support would be lacking
Many of the most basic cellular processes like cell movement, growth, division, formation of intercellular junctions, secretion, and endocytosis all depend on the movement of membrane components and would not be possible if membranes were non-fluid structures. Membrane Fluidity Different types of cellular membranes have their own characteristic lipid compositions from the types of lipids to the nature of the head groups and species of fatty acyl chains
The lipids of a membrane serve as more then structural foundations and can have important biological effects on the membrane
Lipid composition can determine the physical state of the membrane and even influence the activity of the certain membrane proteins
The lipid bilayer also has the ability to self-assemble, a trait used to form liposomes which have been proven to be particularly useful vehicles in drug delivery within the body A less abundant lipid in the membrane then phosphoglyceride
Derived from sphingosine, which is an amino alcohol with a long hydrocarbon chain, linked to a fatty acid to become a ceramide
Different groups can be esterified to the terminal alcohol of the ceramide including phosphorylcholine making sphingomyelin or carbohydrates which make glycolipids
Glycolipids are found on the outer leaflet where they serve as receptors for extracellular ligands and play other crucial roles in cell function Sphingolipids Now known as the “central dogma” of membrane biology
Proteins are shown as either embedded in the membrane, extending through the lipid bilayer as integral proteins or as peripheral proteins or lipid-anchored proteins outside of the lipid bilayer
With the bilayer still present as the core, the membrane’s overall state is now considered fluid
This fluidity allows components the mobility and thus the capability of coming together to engage in various types of interactions The Fluid-Mosaic Model The chemical nature of the membrane was first obtained by Ernst Overton in the 1890s. He found that the dissolving power of the outer layer matched that of a fatty oil.
In 1925 it was proposed by Gorter and Grendel that the membrane was actually a lipid bilayer with polar head groups facing the both the extracellular and cytosolic side of the cell with the hydrophobic tails facing the inside. This was found to be the thermodynamically favored arrangement Membrane Composition Although thin, the plasma membrane shows how its fluid nature enhances its strength against abrasive forces
This again shows the durability of the membrane’s overall structure Proteins vary in the membrane depending on the organelle and cell type
The properties of one surface of a membrane can be very different from the properties of another surface, a property know as sidedness
Proteins that interact with other cells or extracellular substances face the external side of the membrane while proteins that interact with cytoplasmic molecules face the cytosolic side of the membrane
Membrane proteins are classified as either integral, peripheral, or lipid-anchored proteins Membrane Proteins Most membrane lipids contain a phosphate group, which makes them phospholipids
Phospholipids built on a glycerol backbone become phosphoglycerides with an amphipathic character
Unlike triglycerides, diglycerides of the membrane only have two of the hydroxyl groups of the glycerol esterified to fatty acids while the other is esterified to a phosphate group and is known as phosphatidic acid without any other additions
This can be combined with either choline, ethanolamine, serine, or inositol creating phosphatidylcholine PC, phosphatidylethanolamine PE, phosphatidylserine PS, or phosphatidylinositol PI creating the highly water-soluble head group
The fatty acid tails are hydrophobic usually 16 to 22 carbons long and can be either fully saturated, monosaturated, or polysaturated although phosphoglycerides tend to have one unsaturated and one saturated fatty acyl chain. Phosphoglycerides Approximately 20 nonpolar acids amino acids cross the core of the bilayer as a single alpha helix. Not all integral proteins cross as an alpha helix however, but contain a large circular channel amongst membrane-spanning beta strands Are amphipathic and penetrate the lipid bilayer as transmembrane proteins
Have areas on the both the extracellular and cytosolic side of the membrane
Can be receptors, channels or transporters for ions and solutes, or agents that transfer electrons for cellular functions
Aren’t necessarily fixed structures and possess the ability to move laterally in the membrane
Can be separated from the membrane through the use of detergents Integral Proteins This sterol is also a component of the plasma membrane and can compose up to 50 percent of lipid molecules in certain animal cells
It is not present in plant or bacterial cells
The hydrophilic hydroxyl group tends to face the surface of the membrane while the rest of the molecule is embedded in the lipid bilayer
The hydrophobic rings of the molecule are flat rigid and interfere with the movements of the fatty acid tails of the phospholipids Cholesterol
A review of the overall structure of the plasma membrane
And a look into what it can do!!!! Now that we know the basic overall structure….
lets take a closer look!!!! These lipid-protein assemblies held together by noncovalent bonds compose the thin sheet known as the membrane
The bilayer not only acts as a barrier but also serves as the structural backbone of the membrane
The proteins facilitate most of the specific functions of the cell and are highly specialized to depending on the cell type
The lipid to protein ratio also varies with the type of cellular membrane
The leaflets of the bilayer are asymmetrical, as shown by the presence of carbohydrates only on the extracellular side which mediate interactions of the cell as well as their lipid composition The external surface of most membrane proteins, and a small percentage of phospholipids can contain short chains of sugars (glycoproteins and glycolipids). The portions of the protein that extend through the lipid bilayer occur as alpha helices composed of hydrophobic amino acids. The leaflets of the membrane can contain different types of lipids from each other, shown by the differently colored head groups. The thin fragile sheet that separates the cell from its external environment as a continuous unbroken structure
It is responsible for several cellular functions including compartmentalization (1), biochemical locations (2), a selectively permeable barrier (3), solute transportation (4), cell signaling, response and interaction (5), and energy transduction (7)
Organelles within the cell also contain their own plasma membranes What is the plasma membrane? By: Kourtland B. Haile The Plasma Membrane:
Composition and Structure Function The GPI linkages take place in the outer leaflet and extend toward the extracellular side of the membrane while the proteins present on the cytoplasmic side are linked to one or more long hydrocarbon chains embedded in the inner leaflet of the bilayer Also located completely outside of the lipid bilayer on either the extracellular side or cytosolic side
On the cytosolic side, the proteins are held in place by covalent bonds with lipid molecules embedded in bilayer
On the external side of the membrane, proteins are held by glycosyl-phosphatidylinositol (GPI) linkages Lipid-anchored Proteins Have a dynamic relationship with the membrane and can be either recruited to the membrane or released from the membrane depending on conditions Located completely outside of the lipid bilayer, either on the extracellular side or cytosolic side
Interact with the membrane through noncovalent bonds like weak electrostatic forces
The best studied peripheral proteins are found on the cytosolic side of the membrane where they act as a skeleton
Provide mechanical support for the membrane, anchor integral proteins, coat enzymes, and act as transmittance factors for transmembrane signals
Can be separated from the membrane with high concentrated salt solutions Peripheral Proteins Cholesterol Phosphoglyceride Sphingolipid The lipids found in the membrane are extremely diverse and are amphipathic
There are three main types of membrane lipids: Phosphoglycerides, sphingolipids, and cholesterol Membrane Lipids This way of thinking and various experiments led to a new concept in membrane structure… The model first proposed by Gorter and Grendel shows the phospholipids with the water soluble head groups facing the outer surfaces with the hydrophobic fatty acid tails facing the interior. The model proposed by Gorter and Grendel was only part of the puzzle.
Lipid solubility was found to not be the sole determinant in membrane penetration. It was thought that substances could also cross the membrane through the use of protein-lined pores, which would allow polar solutes and ions to enter and leave the cell. Membrane Potential (cont.) Membrane Potential Steroid Hormone Receptors Ligand Gated Channels Named for their interactions with G-proteins
Have 7 transmembrane helices in their structure
The amino-terminus is on the outside of the cell while the carboxyl-terminus is on the inside of the cell.
Three loops on the inside of the membrane form the binding site for intracellular signaling proteins
Three loops on the outside of the membrane form the ligand binding site.
When a ligand binds, a conformational change occurs that causes a complex to form between the G protein and the receptor.
This causes GTP to displace GDP in the active site of the G protein’s α subunit.
This effectively activates the G protein and causes the dissociation of the protein from its receptor and the proteins subunits to dissociate from one another. G Protein-coupled Receptors Receptors bind to extracellular messengers and elicit an appropriate response within the cell.
G protein-coupled Receptors
Receptor Protein-tyrosine Kinases
Ligand Gated Channels
Steroid hormone receptors Receptors Molecules that bind to receptors outside of the cell.
Amino acids and Amino acid derivatives Extracellular Messengers Receptors and Extracellular messengers The Ras-MAP Kinase Pathway Background:
Ras Proteins are important in the following processes: cell division, differentiation, gene expression and transport. What is Ras?
- location: inner surface of the plasma membrane
-made of one subunit Formations:
-"active" form = Ras + GTP
-"inactive" form = Ras + GDP Termination of signal:
-occurs when GTP is hydrolyzed to GDP to stop Ras Ras-MAP kinase cascade: Ras activation 1) A growth factor binds to the RTK receptor and causes autophosphorylation of tyrosine. 2) RTKs (now active) have phosphorylated tyrosines that allow adaptor proteins to "dock"
*Adaptor protein= Grb2 3) Grb2 (adaptor protein) brings Sos protein with it and attaches.
*Sos is a type of GEF (Guanine nucleotide-exchange factor) which binds to an inactive G-protein and causes the GDP to fall off. 4) Grb2 and Sos move from the cytoplasm to the cytoplasmic surface of the plasma membrane. 5) Sos' closeness to the Ras activates it The Ras-MAP kinase Cascade: Raf protein 6) Ras activation opens up a Ras nucleotide-binding site. 7) GDP is released and GTP enters
*Process aided by GEFs as defined earlier 8) The loss of GDP and gain of GTP caues a conformational change which recruits Raf to the inner surface of the plasma membrane 9) Raf protein is phosphorylated/dephosphorylated in order to activate it.
What is RAF?
* a serine-threonine protein kinase The Ras-MAP kinase cascade: Phosphorylation 10) RAF protein phosphorylates MEK 11) MEK phosphorylates 2 MAP Kinases 12) MAP kinases move to the nucleus and phosphorylates/activates transcription and nuclear proteins Review the whole process here! Click next to proceed to the large screen version. Calcium Cellular signaling with IP3 This video provides a general overview of Ca 2+ cellular signaling using the previous processes. Three important components of signaling: 1) Convergence
-diverse receptors can cause similar results (ex-transcription/translation of growth factor)
-a ligand binding to a common receptor can cause various events.
3) Cross talk
-pathways are interconnected and frequently on step on one pathway has an effect on another pathway (ex- cAMP) References: Receptor Protein-Tyrosine Kinases Phosphorylate specific tyrosine residues in protein substrates
Integral membrane proteins that consist of a trans-membrane helix and an extracellular ligand binding domain
When the ligand binds, the protein dimerizes and undergoes autophosphorylation, a process by which the activity of one kinase phosphorylates tyrosine residues on the other, and vice versa.
The causes the activation loop on the protein to move away from the intracellular substrate binding site, allowing the phosphorylation of tyrosine residues on the secondary messenger Conduct the flow of ions or other materials through the membrane.
This can affect the membrane potential or the activities of intracellular enzymes Ligand-regulated transcription factors
Dependent upon the ability of steroid hormones to diffuse across the membrane and bind to the receptor, which exists within the cell.
This binding results in a conformational change, causing the complex to move to the nucleus and bind either to promoter components or other components that modify gene transcription. Used by cells called neurons to propagate nerve impulses
Resting potential- normal membrane potential of a nerve or muscle cell caused by K+ gradients maintained by the Na+/K+-ATPases of the cell
The voltage equivalent of the concentration gradient for specific ions can be calculated using the Nerst Equation
The negative resting potential for a cell is usually near the negative Nerst potential for K+ Membrane depolarization is caused by the stimulation of the cell and the subsequent opening of the Na+ channels in the cell.
This triggers the action potential of the cell
The opening of a Na+ channel causes the activation of a neighboring Na+ channel, resulting in the movement of the action potential across the membrane of the cell.
The Na+ channels become inactivated following the action potential as the membrane re-equilibrates, producing a refractory period where the membrane is incapable of stimulation. GPCR G-protein Mute your computer because the music is just awful. But the video is great! Karp, G. Cell and molecular biology, concepts and experiments. 6th. Hoboken: Wiley, 2010. Print.
Evans-Anderson, H. 2013. Cell Biology Notes. Winthrop University.
-(Awesome) Hand-drawn pictures by Kara Hardwick (2009; 2013)
Imageshttp://www.sciencephoto.com/image/493095/530wm/C0150850-Cell_nucleus,_TEM-SPL.jpghttp://endosymbiotichypothesis.files.wordpress.com/2010/09/mitochondria.gif http://www.sciencephoto.com/media/214982/view http://www.sciencephoto.com/media/214823/view http://www.peroxisomedb.org/ http://ghr.nlm.nih.gov/condition/zellweger-spectrum http://www.sciencephoto.com/media/235743/view http://www2.iib.uam.es/rescalante_lab/Sitio_web/Research.html http://www.sciencephoto.com/media/79660/enlarge http://www.sciencephoto.com/media/410066/view http://www.sciencephoto.com/media/215034/enlarge http://en.wikipedia.org/wiki/Tubulin http://www.sciencephoto.com/media/209939/enlarge http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002390/