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DNM1 gene

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Yara Arias

on 14 October 2013

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Transcript of DNM1 gene

DNM1 gene
DNM1
DNM1 is a gene that codes for the Dynamin 1 protein and is a crucial constituent in vesicle formation in receptor-mediated endocytosis, synaptic vesicle recycling and mitochondrial fission. It is found on the 9th chromosome with a cytogenetic location of 9q34.11. It has 51,870 base pairs and is more precisely located
from base pair 130,965,658 to base pair 131,017,528 on chromosome 9.
Dynamin
Visuals
Mitochondria are important structures that go through cycles of fission and fusion continuously throughout the life of a cell. Mitochondria are the cells power producers. Mitochondrial division is important for the remodeling and rearrangement of mitochondrial networks, as well as for enabling mitochondrial segregation during cell division. Levels of nutrients and other criteria can tip the balance toward either fusion or fission.
DNM1 helps with fission by binding to the mitochondria's outer membrane and squeezing it until it splits in two.
DNM1 forms spirals that are structurally tailored to fit mitochondria.

Dnm1 is amongst 3 top players in mitochondrial fission and fusion.
Mitofusions = outer mitochondrial membrane fusion
OPA1/Mgm1 = inner mitochondrial membranes
DRP1/DNM1 = division of outer and inner mitochondrial membranes
Mitochondria
DNM1 encodes for the dynamin 1 protein which is a sub-family of GTP binding proteins that is required for mitochondrial fission. GTPases are often coupled to G proteins and have essential roles in signal transduction, translocation, protein synthesis, differentiation, vesicular transport regulation and control of cell growth. G proteins (guanine nucleotide-binding proteins) are a family of proteins involved in transmitting chemical signals outside the cell and causing changes inside the cell. Dynamin is a globular cytosolic protein that is involved in vesicle trafficking, caveolae internalization, synaptic vesicle recycling, and receptor-mediated endocytosis. Dynamin assembles on the cytoplasmic side of the mitochondrial tubules at sites in which cell division will occur. It has a molecular-motorized assembly that tightens and lengthens around the neck of clathrin-coated pits and assists in pinching vesicles from the plasma membrane. Clathrin is a coat protein that performs important roles in shaping rounded vesicles in the cytoplasm for intracellular trafficking. Clathrin-coated vesicles sort cargo at the cell membrane and have a special shape called triskelion, which is a cage like structure. The energy that dynamin has to twist and pinch comes from the hydrolysis of GTP. This role would make dynamin unique among GTPases in its ability to act as a mechanochemical enzyme. After dynamin subunits polymerize around the neck of the pit, hydrolysis of GTP regulates contraction of the polymeric dynamin until the vesicle pinches off. Clathrin and dynamin depolymerize after the vesicle detaches from the membrane and are reused by the cell.
GTP
In the presence of GTP, dynamin tubes lengthen and tighten around the vesicle neck.
GDP
In the presence of GDP, dynamin tubes are large and relaxed.
Mutation of dynamin 1 results in it failing to pinch off the vesicle from it's parent membrane. Mutant dynamin block endocytosis after the initiation of coat assembly, but before coated pit invagination. Vesicle coating is unaffected in cells over expressing those dynamin 1 mutations. The sequence is coat assembly, receptor recruitment (which is where the mutation takes place), coated pit invagination and finally vesicle budding. The mutations lead to accumulation of clathrin-coated pits with excessively long necks that are surrounded by polymeric dynamin 1 but do not pinch off.
Mutations
Several human genetic nuerodegenerative diseases are associated with improper regulation of mitochondrial fusion or fission.
Alzheimer's disease
Neuronal Intranuclear Inclusion disease
Nuerodegeneration
References


Karen G. Hales, Ph.D. (Dept. of Biology, Davidson College) Mitochondrial Fusion and Division. Nature Education 3(9):12

Bereiter-Hahn, J. & Voth, M. Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria. Microscopy Research and Technique 27, 198–219 (1994).

J. E Hinshaw. et al. Dynamin and its Role in Membrane Fission. Annual Reviews Collection: National Center for Biotechnology (US); 2002 Nov.

Ceresa B P, Kao A W, Santeler S R, Pessin J E. Inhibition of clathrin-mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways. Mol. Cell Biol. 1998;18:3862–70.

Daniels G M, Amara S G. Regulated trafficking of the human dopamine transporter Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters. J. Biol. Chem. 1999;274:35794–801.

Hinshaw J E, Schmid S L. Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding. Nature. 1995;374:190–92.

National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/gene/1759












Dynamin Domains
Dynamin 1
Characteristics
right-handed
flexible
helical
molecularly motorized
twisting motion
sphere shape
cytosolic protein
tetramer that transforms into rings and spirals
force generator
Size = 864 amino acids
Subcellular location = cytoplasm
Alternative symbol = DNM
Gene type = protein coding
Molecular weight = 97.4106 kD
Yara Arias
Cell Physiology 3301-001

Fission & Fusion
Fission:
the act of cleaving or splitting into two parts.

Fusion:
the joining together and becoming one.
Other reasons why the mitochondria is important:
ATP generation
Ca++ maintenance
Induction of apoptosis (cell suicide)
Receptor-Mediated Endocytosis
Receptor-mediated cytosis takes place when a cell brings in molecules from its surroundings. It does so to obtain nutrients, remove signaling molecules or destroy foreign invaders. These substances are brought into the cell via membrane enclosed vesicles after they are broken down by lysosomes. This process is known as receptor-mediated endocytosis because of high specificity receptors that must recognize the substances that need to enter the cell. The internalization sequence on the receptors interact with adaptins once the ligands (the particles that are to be internalized) are intact. Adaptins are the molecules that start the process of vesicle formation and also attract the clathrin (coat protein). This is were our subject player enters the arena.
Dynamin comes in and positions itself around the clathrin coated pits
. Once it is in position, GTP hydrolysis activates dynamin's pinching effect until the vesicle is unattached from the membrane.
Dynamin Family
Members
Dynamin
: Synaptic vesicle recycling, receptor meditated endocytosis, caveolae internalization and trafficking in and out of the Golgi
Dmn1
: mitochondrial morphology
Drp1
: mitochondrial morphology
VPS1
: vesicle formation at the Golgi
Mgm1
: mitochondrial morphology
Mx1
: inhibition of viral RNA transcriptiion
Human dynamin-like protein
: cell signaling
3 Isoforms
Dynamin 1: found in neuronal tissue

Dynamin 2: ubiquitously expressed

Dynamin 3: predominately in the
testis, but also found in neurons and the lungs
Cells expressing dynamin mutants deficient in GTP binding resulted in clathrin-coated pits failing to invaginate. Cells were also unable to internalize tranferrin.
Dynamin Mutants
K44A
: an inhibitor of endocytic vesicle format
K44E
: prevents microtubule-induced focal adhesion disassembly



S45N
: potently inhibit CME and effectively recruit other
endocytic accessory proteins to stalled coated pits

DK44
: lead to inhibition of clathrin-mediated endocytosis
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