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Clathrin mediated endocytosis

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matthew lawson

on 20 November 2012

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Transcript of Clathrin mediated endocytosis

Clathrin Endocytosis is a process that imports extracellular molecules by forming vesicles from
plasma membrane. Many eukaryotic cells carry out endocytosis as a means of taking up
macromolecules and other substances from the extracellular medium. In the process,
a small segment of plasma membrane folds inward progressively and it pinches off to
form an endocytic vesicle containing ingested substances or particles. By this process, materials that were previously outside the cell are brought into the cell.

Endocytosis is important for several cellular processes including ingestion of essential
nutrients and defense against microorganisms.

Endocytosis encompasses 3 different processes that differ in the nature of the material
ingested and the mechanism employed and they are Pinocytosis, Phagocytosis and
Receptor-mediated endocytosis. Introduction A coated-vesicle plays a major role in diverse cellular processes. It is involved in vesicular traffic throughout the endomembrane system as well as transport during exocytosis and endocytosis.
A Clathrin coated vesicle (CCV) has a layer of Clathrin on the cytosolic side of the membrane surrounding the vesicle. Clathrin, the coat protein, participates in several steps of the formation of transport vesicles.

The main functions of CCVs is to constitutee cycling of plasma membrane in cells, and to uptake extracellular fluid (fluid phase endocytosis). They are also able to accumulate plasma membrane proteins containing ‘endocytosis signals’. These proteins that are often cell surface receptors and have ligands associating with them, are internalized very efficiently in Receptor-mediated Endocytosis. Clathrin coats are composed of three principal sets of protein components:

1. The main scaffold protein is clathrin, which contains a 190 kDa heavy chain associated with a light chain of »24–27 kDa. These heavy chain/light chain complexes form three-legged trimers, the clathrin triskelions (as can be seen in figure x), which can oligomerize both in vivo and in vitro.

2. The clathrin adaptor (AP) complexes and assembly protein AP180 also contribute to the coat scaffold. AP complexes can nucleate clathrin cage assembly, link clathrin to the membrane, and interact with membrane proteins containing endocytosis signals. Four different AP complexes have been identified. AP1 and AP2 are associated with Golgi-derived CCVs and endocytic CCVs, respectively. The functions of the other AP complexes, AP3 and AP4, are still to be clearly established. A second set of adaptor proteins associated with endocytic coated pits are the nonvisual arrestins. Arrestins transmit signals via, seven transmembrane domain (7TM), G protein-coupled receptors.

3. In addition to these scaffold proteins, a number of accessory proteins function in coordinating the assembly of the clathrin lattice, reorganizing the lattice to drive invagination, defining the size of CCVs, scission, uncoating and recycling. These accessory proteins include dynamin, Eps-15, epsin, synaptojanin, amphiphysin, the endophilins, and the Dap160/Intersectin/Ese proteins. Figure 4. Diagram of arrangement of clathrin triskelions in a hexagonal barrel. Four triskelions are indicated in different colours. In vivo coated vesicles are larger. The minimum composition required to accommodate a vesicle is believed to be 12 pentagons and 20 hexagons containing 60 triskelions, a mixture of hexagons and pentagons being necessary to achieve curvature. The proximal leg domains from adjacent hubs form an antiparallel pair on the top of each edge and the distal domains make an antiparallel pair beneath. Introduction Components of Clathrin/
adaptor protein complex Clathrin Coat Components:
Two oligometric protein complexes; clathrin and adaptor proteins (APs). Clathrin is a three legged molecule, consisting of C-terminal connection of three elongated heavy chains (HC) and each in association with a light chain (LC). The clathrin have a very distinct shape, a triskelion (Figure Z) which is well suited for combining together into polygonal arrays. Adaptor protein complexes act both in clathrin assembly and for receiving materials for transport. Two Aps types has been identified in relation to clathrin coating , one in the plasma membrane; Adaptor Protein-2(AP-2) and the other localized in the trans-Golgi networks, TGN; Adaptor Protein-1(AP-1). At physiological ionic conditions adaptor proteins bind to clathrin and induce assembly. Specifically, the assembly activity is due AP β subunit which stimulates the clathrin to form cages. AP works as adaptors that relate coat formation to cargo incorporation; this is due to the ability of AP to recognize the sorting sequences on transmembrane cargo proteins Adaptor Proteins
“Protein complexes that cover the cytosol-facing surface of clathrin-coated vesicle membranes of the plasma membrane and trans Golgi network.”

These adaptors can simultaneously bind to clathrin and to transmembrane proteins and/or phospholipids, primarily phosphatidylinositol (4,5)-bisphosphate (PIP2).

Adaptors can also interact with each other and with other components of the coated-vesicle machinery, to provide dynamic regulation of clathrin-mediated endocytosis.

Intracellular clathrin-coated vesicles contain AP-1 or AP-3 adaptors whereas endocytic clathrin-coated vesicles contain AP-2 adaptors.

A layer of these adaptors exists between the clathrin lattice and the surface of the vesicle. AP2 is the most well studied adaptor protein directly involved with clathrin-mediated endocytosis. The protein consists of multiple sub-units that have different functions; the alpha-2 and beta-2 adaptin subunits (large), the mu-2 sub-unit (medium) and the sigma-2 sub-unit (small).

AP2 associates with the plasma membrane and is responsible for endocytosis by regulating and coordinating coated-vesicle formation, most likely, regulation occurs by a PIP2 binding site within the mu-adaptin subunit. This phosphoinositide has been implicated because experiments have shown that a mutant mu-adaptin will inhibit receptor-mediated endocytosis in living cells.

The large subunits (the adaptins) are divided into three domains: the N-terminal domain, the hinge domain, and the C-terminal appendage. The alpha-adaptin subunit is responsible for binding to the PIP2 lipids in the plasma membrane, while the beta-adaptin is responsible for recruiting clathrin molecules through the clathrin-binding sequence; the clathrin box which lies in the hinge region. Accessory proteins are also involved with the process; Epsin and AP180 (and its homologue CALM) are most often implicated with reference to clathrin-mediated endocytosis, but other accessory proteins include EPs-15, amphphysin, HIP1 and dab 2.

These accessory proteins, along with HIP1 have an Epsin N-terminal homology domain (ENTH) which is the region that is thought to bind PIP2 in clathrin-mediated endocytosis
HIP1 is a neuronal protein (implicated in huntington’s disease) that likely has a role in clathrin-mediated endocytosis in neurones. In the case of the accessory proteins Epsin 1 and 2, clathrin binding is to the N-terminal domain of the clathrin heavy chain (CHC) and is mediated in part via the clathrin box.

The ENTH has a strong affinity for PIP2 and plays a crucial role in clathrin-mediated endocytosis, the precise details of this process are as of yet unknown, it has however been shown that interaction between ENTH and PIP2 is essential for clathrin-mediated endocytosis to occur.

AP180 and CALM are accessory proteins that are known to promote clathrin and AP2-binding as flat lattices because they possess the N-terminal domain for binding of PIP2. Receptor Mediated Endocytosis by Clathrin Coated Vesicles 1. What is Endocytosis? 3. What is Clathrin? 4. What is a Clathrin-Coated Vesicle? Adaptor Protein 2 (AP-2) Accessory Proteins Dynamin Dynamin is a large GTPase involved in the process of membrane fission; allowing the budding vesicle to become seperated from the membrane.

Fission by dynamin is a three step process:
1. Assembly of the dynamin helix around the neck of the budding vesicle. This is controlled by GTP concentration and torque.
2. Constriction of the dynamin helix
3. The breaking of the neck, controlled by membrane elasticity - tension and rigidity. Figure 10. A diagram showing a quick overview of the steps involved in vesicle budding and fission via dynamin. 1. What is endocytosis? Clathrin is a protein that plays an important role in forming coated-vesicles in receptor-mediated endocytosis.
Clathrin exists as a lattice and the basic structural unit of it is a three-legged structure called Triskelions. A triskelion is a mutlimeric protein that composed of 3 heavy chains and 3 light chains radiating from a central vertex.
The heavy chains form legs of clathrin with a globular domain at the outer tip and the light chains bound to the inner half of each leg. Clathrin triskelions assemble into a lattice of pentagons and hexagons structures characteristics of coated pits and vesicles. Endocytosis is a process that imports extracellular molecules by forming vesicles from plasma membrane. Many eukaryotic cells carry out endocytosis to take up macromolecules and other substances from the extracellular medium. In the process, a small segment of plasma membrane invaginates, then it pinches off to form an endocytic vesicle containing ingested substances or particles. By this process, materials that were previously outside the cell are brought into the cell.
Endocytosis plays an important role for several cellular processes, such as essential nutrients ingestion and defense against microorganisms.

Endocytosis encompasses 3 different processes that differ in the nature of the material ingested and the mechanism employed as figure 2 shows they are Pinocytosis, Phagotcytosis and Receptor-mediated Endocytosis. 2. What is Receptor-mediated Endocytosis? Functions of Clathrin
in Endocytosis Receptor-mediated endocytosis is a process to concentrate and ingest extracellular molecules by means of specific receptors on the outer surface of plasma membrane. In eukaryotic cells, it acts as primary mechanism for specific internalisation of most macromolecules. One example is in mammalian cells, they can ingest hormones, growth factors, enzymes, serum proteins, antibodies, iron, and even some viruses and bacterial toxins by this mechanism depending on cell type.

Receptor-mediated endocytosis (RME) is dependent on the interaction of ligands with specific
receptors expressed on the cell surface. It operates in most cells and is involved in a large number of cellular functions including the acquisition of essential nutrients such as iron, antigen processing, growth factor receptor regulation, clearance of modified extracellular macromolecules, transcytosis, and synaptic transmission and remodelling. RME is also associated with various pathological conditions which it provides a route into cells for bacterial, protozoan and viral pathogens, and many bacterial and plant toxins. In addition, RME has been linked to conditions such as hypertension, Alzheimer and prion diseases, and cancer.

Huntingtin interacting protein (HIP1) is an a protein that binds to the clathrin heavy chain and AP2, crucial componets of the clathrin coat. HIP1 interacts with the huntingtin protein which is mutated in Huntington's disease. HIPI acts as a cofactor for the endocytic process, specifically as a cofacotr in clathrin coat asembly. In Huntington's disease the mutant protein binding to HIPI significantly impacts of HIP1's function, therefore disrupting endocytosis in the neurons, ultimatley dirupting cell function. In this disease the recognition signal for AP2 in the cytoplasmic domain of the low density lipoprotein is mutated, leading to a lack of cholertserol endocytosis and an accumulation the lipoproteins in the blood. Influenza and other viruses Influenza and Sinibis virus can only infect cells when the endocytotic pathway is active. Influenza fuses with the late endosomes whereas Sinibis virus fuse with the early endosomes.
Viruses follow the course of their attachment receptors until the low pH in early or late endosomes triggers the fusion and delivery of the viral capsids to the cytoplasmic site of replication.
Entry into the acidic endosomes induces a conformational change in the viral protein hemaglutinin, which mediates viral envelope fusion and delivery of viral RNA into the cytosol.
Foot and Mouth Disease and Hepatitis C also enter via clathrin mediated endocytosis Cholera toxin B subunit induces formation of clathrin coated pits and vesicles, and internalised into an endosomal compartment, poisoning cells and causing disease. Cholera Caused by a defective gene in the protein HFE (Human hemochromatosis protein) . Usually it binds transferrin receptors and regulated its ability to internalise iron-loaded transferin, the mutated protein is unable to bind to the transferrin receptor, therefore iron is not internalised into cells via the clathrin pathway. Clathrin vesicles are more persistent in mature neurons, affecting cellular responses to extracellular signals as the receptors at the plasma membrane are regulated in an altered fashion. Because clathrin mediated endocytosis is involved in transferrin uptake, poorly regulated clathrin mediated endocytosis in aging cells may be implicated in the iron deposition in the brains of Parkinson’s and Alzheimer’s disease. Evidence for the localisation of clathrin light chains on Alzheimer’s plaques, also the disruption of CME can lead to failures in neuron signalling , which may contribute to the symptoms of Alzheimer’s. Clathrin may contribute to brain degeneration in picks disease, which is characterised by corticobasal degeneration and protein deposition in the form of picks bodies. Clathrin light chains have been found in these picks bodies, this suggests that mis-localisation events contribute to the disease. Hypercholesterolemia Hemochromatis Huntington's Disease Neurodegeneration Transferrin Alzheimer’s Disease Picks Disease
Clathrin coats are involved in at least two transport steps:

1. Endocytosis from the plasma membrane to early endosomes and transport between the trans-Golgi network (TGN) and endosomes (figure 5).
2. Clathrin coats may also function in transport from endosomes, maturing secretory granules and other cellular sites. Clathrin Coated vesicles (CCVs) have two principal functions.
1. They provide a scaffold that can deform a membrane to generate small (60–100 nm diameter), high curvature vesicles (see below in figure 4).
2. They select the cargo to be transported by these vesicles. For endocytic CCVs the cargo includes proteins that must be internalized from the cell surface (e.g. receptor–ligand complexes), as well as components of the machinery that allows the vesicles to dock and fuse with early endosomes and the lipid matrix in which these proteins reside. Recommended reading/ sources for clathrin protien:
Basic outline of the protein plus adaptor proteins via link on page: http://www.ebi.ac.uk/interpro/potm/2007_4/Page1.htm
another overview of Clathrin mediated endocytosis: http://www.abcam.com/index.html?pageconfig=resource&rid=10236&pid=14
Marsh, M. (2001). Clathrin-coated Vesicles and Receptor-mediated Endocytosis. In: encyclopedia of Life Sciences [Online]. url: http://onlinelibrary.wiley.com/doi/10.1038/npg.els.0000555/full (A more detailed outline of clathrin and the process of endocytosis)
Zhang, J., J. Fan, et al. (2012). "Characterization of two distinct modes of endophilin in clathrin-mediated endocytosis." Cellular Signalling 24(11): 2043-2050. url: http://www.sciencedirect.com/science/article/pii/S0898656812001787 (very recent article doing research into the process of clathrin mediated endocytosis)
(NB too access some of the articles you will be requied to log in to your cardiff portal account) The chief function of clathrin coated vesicles is to assist in the transport of substances between the trans-Golgi network, the endosomes and the plasma membrane. The intake of cargo from outside the cell is essential to normal cell functioning and clathrin-dependent endocytosis is heavily relied on in cells where this activity is especially high. The role of clathrin vesicle biogenesis can be clearly seen in nerve cells, especially at the terminus, where they have the important function of allowing the recycling of neurotransmitters used in action potentials by endocytosis of the used molecule. Clathrin mediated endocytosis is so active in these cells that they are commonly used as models of the process. The rapid turnover of neurotransmitter in these cells requires the efficient mechanism of using clathrin to form the scaffolding of the vesicles as figure 11 shows below. Figure 11 showing the formation of the clathrin scaffold around the vesicle as it is budding off the membrane. Image from: Kaksonen, M. Toret, C. Drubin, D. (2006). Nature Reviews Molecular Cell Biology 7.
url: http://www.nature.com/nrm/journal/v7/n6/fig_tab/nrm1940_F4.html Another example of the use of clathrin coated vesicles is the intake of cholesterol in low density lipoproteins. Low density lipoproteins are covered in receptors for clathrin-coated vesicle formation. Many also contain areas with microvilli to increase surface area and therefore the speed with which cholesterol can be endocytosed by the cell. Clathrin-independent endocytosis

Although clathrin dependent endocytosis is the most common and best studied mechanism of endocytosis it is not the only one. There are many which don’t involve clathrin at all and it is these which are occasionally hijacked by viruses or bacteria to gain access to a host cell. One pathway is the use of caveolin to form the scaffolding for the vesicle; however the vesicles formed by this method are smaller than clathrin-coated vesicles which have obvious disadvantages. Just like clathrin-dependent endocytosis, dynamin is used in the fission of the vesicle from the plasma membrane.

Another method of entry into cells is phagocytosis where instead of budding inwards the plasma membrane extends outwards and surrounds the particles. This involves actin and is completely distinct from clathrin vesicles and is more commonly used for endocytosis of bacterial cells for destruction. Pathology Alzheimer's Plaque Lipids Figure 1. from:
(also some basic info on this wiki page related to endocytosis) AP-2 and the Accessory Protein AP180 Reference List: Figure 6: Showing the structures of the key parts of receptor mediaited endocytosis by clathrin coated vesicles. Image A: the formations of a CCV, Image B: Clathrin triskelion, C: AP2
D: A 21 Å resolution map of clathrin assembled into cages obtained by cryo-electron microscopy. The image has been coloured to show the disposition of a single triskelion.
E: Crystal structure of the AP2 adaptor.
from: Puertollano, R. 2004. EMBO reports url:
http://www.nature.com/embor/journal/v5/n10/fig_tab/7400249_F1.html These are perhaps the most well known examples of how adaptor proteins and accessory proteins work together to promote clathrin assembly. AP-2 and AP180 work in nerve terminals to promote clathrin assembly.
AP-2 and AP180 have been shown to interact directly to form an AP180-AP-2 complex that is much more efficient at assembling clathrin than either of the proteins alone.
It have been found that AP180 directly interacts with both the hinge domain of the alpha- subunit and with the beta-subunit. Figure 8: This shows a more detailed view of the AP-2 adaptor and associated accessory proteins. The DPF and DPW sites are sequence motifs thought to affect binding of certain accessory proteins to the alpha-arms of the AP-2 Adaptor. Figure 5. showing the overall process of endocytosis and where Clathrin/CCVs are used. from:
Barth, D. (2006). D. Sato, M. Intracellular trafficking. WormBook, ed.
url: http://www.wormbook.org/chapters/www_intracellulartrafficking/intracellulartrafficking.html References and Further Reading - This article has a lot of detailed information about adaptor proteins; http://jcs.biologists.org/content/119/18/3719.full References and Further Reading - A very recent article regarding the details pertaining to dynamin fission of Clathrin-coates vesicles:
http://www.cell.com/abstract/S0092-8674(12)01124-5 Reference - introduction:
1.Becker, W.M., Kleinsmith L.J., Hardin, J. (2006). The World of The Cell. 6th ed. St. Francisco: Pearson Education.

2.March, M. (2001). Clathrin-coated Vesicles and Receptor-mediated Endocytosis. eLS [Online].

References clathrin:
Marsh, M. (2001). Clathrin-coated Vesicles and Receptor-mediated Endocytosis. In: encyclopedia of Life Sciences [Online].
Garaiova, Z., S. P. Strand, et al. (2012). "Cellular uptake of DNA-chitosan nanoparticles: The role of clathrin- and caveolae-mediated pathways." International Journal of Biological Macromolecules 51(5): 1043-1051.
Zhang, J., J. Fan, et al. (2012). "Characterization of two distinct modes of endophilin in clathrin-mediated endocytosis." Cellular Signalling 24(11): 2043-2050.

References components:
1. Collins BM, McCoy AJ, Kent HM, Evans PR, Owen DJ: Molecular architecture and functional model of the endocytic AP2 complex. Cell 2002, 109:523-535.
2. Smythe E: Clathrin-coated vesicle formation: a paradigm for coated-vesicle formation. Biochem Soc Trans 2003, 31:736-739.
3. Pishvaee, B; Payne, GS: Clathrin Coats— Threads Laid Bare. CELL 1998 Volume: 95 Issue: 4 Pages: 443-446
4. R.A Crowther, B.M Pearse. Assembly and packing of clathrin into coats; J. Cell Biol, 91 (1981), pp. 790–797

Adaptor protein/ Dynamin research

Rohde, G., Wenzel, D., Haucke, V. 2002. A phosphatidylinositol (4,5)-bisphosphate binding site within μ2-adaptin regulates clathrin-mediated endocytosis. Journal of Cell Biology. Volume 158

Jackson, T. A review of how research into the components of the clathrin coat has provided insights into the operation of these molecular machines

Ohno, H. Clathrin-associated adaptor protein complexes Journal of Cell Science 2006 Issue:

Owen D. J., Collins B. M., Evans P. R. 2004. Adaptors for clathrin coats: structure and function. Annu Rev Cell Dev Biol.;20:153-91. .

Metzler, M., Legendre-Guillemin, V., Gan, L., et al. 2001. HIP1 Functions in Clathrin-mediated Endocytosis through Binding to Clathrin and Adaptor Protein 2. The Journal of Biological Chemistry. Volume 276.
Itoh, T., Koshiba, S., Kigawa, T., et al. 2001. - Role of the ENTH Domain in Phosphatidylinositol-4,5-Bisphosphate Binding and Endocytosis. Science. Volume 291.

Dynamin - http://www.nature.com/index.html?file=/nrm/journal/v5/n2/abs/nrm1313_fs.html

Morlot, S., Galli, V., Klein, M., et al. 2012. Membrane Shape at the Edge of the Dynamin Helix Sets Location and Duration of the Fission Reaction. Cell. Volume 151.

Hao, W., Luo, Z., Zheng, L., et al. 1999. AP180 and AP-2 Interact Directly in a Complex That Cooperatively Assembles Clathrin. The Journal of Biological Chemistry. Volume 274.

Brett, T., Traub, L,. Fremont, D. 2002. Accessory Protein Recruitment Motifs in Clathrin-Mediated Endocytosis. Cell Press, Volume 10. .

Functions references:


Comparative proteomics of clathrin-coated vesicles: Georg H.H. Borner, Michael Harbour, Svenja Hester, Kathryn S. Lilley, Margaret S. Robinson J Cell Biol. 2006 November 20; 175(4): 571–578. doi: 10.1083/jcb.200607164

Biological basket weaving: formation and function of clathrin-coated vesicles: Brodsky FM, Chen CY, Knuehl C, Towler MC, Wakeham DE. : Annu Rev Cell Dev Biol. 2001;17:517-68.

Clathrin-dependent endocytosis: Seyed Ali MOUSAVI, Lene MALERØD, Trond BERG and Rune KJEKEN: Biochem. J. (2004) 377, 1–16.

Beta very low density lipoprotein and clathrin-coated vesicles co-localize to microvilli in pigeon monocyte-derived macrophages. Landers SC, Jones NL, Williams AS, Lewis JC.: Am J Pathol. 1993 May;142(5):1668-77.

Pathways of clathrin-independent endocytosis: Satyajit Mayor and Richard E. Pagano: NATURE REVIEWS, MOLECULAR CELL BIOLOGY, VOLUME 8, AUGUST 2007 - 603

pathology references:
Young, A. (2007) Structural insights into the clathrin coat. Seminars in Cell & Developmental Biology 18: 448-458.
Meertens, L., Bertaux, C. and Dragic, T. (2006) Hepatitis C virus entry requires a critical postinternalisation step and delivery to early endosomes via clathrin-coated vesicles. Journal of Virology 80: 11571-11578.

Hansen, G. H., Stine-Mathilde, D., Rasmussen, C. R., Immerdal, L., Niels-Christiansen, L. et al.(2005) Cholera toxin entry into pig enterocytes occurs via a lipid raft and clathrin dependant mechanism. Biochemistry 44: 873-882.

DeTulleo, L. and Kirchhausen, T. (1998) The clathrin endocytic pathway in viral infection. The EMBO Journal 17: 4585-4593.

Legendre-Guillemin, V., Metzler, M., Lemaire, J. F., Philie, J., Gan, L., Hayden, M. R. and McPherson, P. S. (2004). Huntingtin interacting protein 1 (HIP1) regulates clathrin assembly through direct binding to the regulatory region of the clathrin light chain. Journal of Biological Chemistry 280: 6101-6108.

Erdmann, K. S., Mao, Y., McCrea, H. J., Zoncu, R., Lee, S., Paradise, S., and Modregger, J. et al. ( 2007). A role of the lowe syndrome protein OCRL in early steps of the endocytic pathway. Developmental Cell 13: 377-390.

Brodsky, F. M., Chen, C. Y., Knuehl, C., Towler, M. C. and Wakeham, D. E. (2001). Biological basket weaving: formation and function of clathrin-coated vesicles. Annual Review of Cell Developmental Biology 17: 517-568.

Rao, D. S., Chang, J. C., Kumar, P. D., Mizukami, I., Smithson, G. M., Bradley, S. V., Parlow, F. et al. (2001). Huntingtin interacting protein 1 is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors. Molecular and Cellular Biology 22: 7796-7806.

Metzler, M., Legendre-Guillemin, V., Gan, L., Chopra, V., Kwok, A., McPherson, P. S. and Hayden, M. R. (2001). HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2. Journal of Biological Chemistry 276: 39271-39276. This and other uptakes via clathrin mediated endocytosis can be seen in figure 13 below. Figure 13 showing various uptake methods into cells via endocytosis. 1. Figure 2. Figure 3. Figure 7. the structure of the AP2 adaptor from:
http://www.abcam.com/index.html?pageconfig=resource&rid=10236&pid=14 Figure 9. Figure 12. an image of an alzheimers plaque
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