Clathrin

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Clathrin
Identifiers
Symbol ?
Other data
Locus Chr. 12 q23-q24
clathrin, light polypeptide (Lcb)
Identifiers
Symbol CLTB
Entrez 1212
HUGO 2091
OMIM 118970
RefSeq NM_001834
UniProt P09497
Other data
Locus Chr. 4 q
Clathrin light chain
Identifiers
Symbol Clathrin_lg_ch
Pfam PF01086
InterPro IPR000996
PROSITE PDOC00196
Clathrin coat structure
clathrin, heavy polypeptide (Hc)
Identifiers
Symbol CLTC
Alt. symbols CLTCL2
Entrez 1213
HUGO 2092
OMIM 118955
RefSeq NM_004859
UniProt Q00610
Other data
Locus Chr. 17 q11-qter
Mechanism of clathrin-dependent endocytosis.
clathrin, heavy polypeptide-like 1
Identifiers
Symbol CLTCL1
Alt. symbols CLTCL
Entrez 8218
HUGO 2093
OMIM 601273
RefSeq NM_001835
UniProt P53675
Other data
Locus Chr. 22 q11.2
Clathrin propeller repeat
PDB 1utc EBI.jpg
clathrin terminal domain complexed with tlpwdlwtt
Identifiers
Symbol Clathrin_propel
Pfam PF01394
Pfam clan CL0020
InterPro IPR022365
SCOP 1bpo
SUPERFAMILY 1bpo
Clathrin heavy-chain linker
PDB 1utc EBI.jpg
clathrin terminal domain complexed with tlpwdlwtt
Identifiers
Symbol Clathrin-link
Pfam PF09268
Pfam clan CL0020
InterPro IPR015348
SCOP 1utc
SUPERFAMILY 1utc

Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975.[1] It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice that surrounds the vesicle. Coat-proteins, like clathrin, are used to build small vesicles in order to safely transport molecules within and between cells. The endocytosis and exocytosis of vesicles allows cells to transfer nutrients, to import signaling receptors, to mediate an immune response after sampling the extracellular world, and to clean up the cell debris left by tissue inflammation. On occasion, this mechanism also provides a pathway for raiding pathogens or toxins.

Structure[edit]

The clathrin triskelion is composed of three clathrin heavy chains and three light chains interacting at their C-termini. The three heavy chains provide the structural backbone of the clathrin lattice, and the three light chains are thought to regulate the formation and disassembly of a clathrin lattice.

Clathrin heavy chain is, in concept, broken down into multiple subdomains, starting with the N-terminal domain, followed by the ankle, distal leg, knee, proximal leg, and trimerization domains. The N-terminal domain consists of a seven-bladed β-propeller structure. The other domains form a super-helix of short alpha helices. This was originally determined from the structure of the proximal leg domain that identified and is composed of a smaller structural module referred to as clathrin heavy chain repeat motifs. The light chains bind primarily to the proximal leg portion of the heavy chain with some interaction near the trimerization domain.

When triskelia assemble together in solution, they can interact with enough flexibility to form 6-sided rings that yield a flatter lattice, or 5-sided rings that are necessary for curved lattice formation. When many triskelions connect, they can form a basket-like structure. The structure shown above, is built of 36 triskelia, one of which is highlighted in green.

In a cell, a triskelion floating in the cytoplasm binds to an adaptor protein, linking one of its three feet to the membrane at a time. This triskelion will bind to other membrane-attached triskelia to form a rounded lattice of hexagons and pentagons, reminiscent of the panels on a soccer ball, that pulls the membrane into a bud. By constructing different combinations of 5-sided and 6-sided rings, vesicles of different sizes may assemble. The smallest clathrin cage commonly imaged, called a mini-coat, has 12 pentagons and only two hexagons. Even smaller cages with zero hexagons probably do not form from the native protein, because the feet of the triskelia are too bulky.

Function[edit]

Like many proteins, clathrin represents a perfect case of form following function; it performs critical roles in shaping rounded vesicles in the cytoplasm for intracellular trafficking. Clathrin-coated vesicles (CCV) selectively sort cargo at the cell membrane, trans-Golgi network, and endosomal compartments for multiple membrane traffic pathways. After a vesicle buds into the cytoplasm, the coat rapidly disassembles, allowing the clathrin to recycle while the vesicle gets transported to a variety of locations.

Adaptor molecules are responsible for self-assembly and recruitment. Two examples of adaptor proteins are AP180[2] and epsin.[3][4][5] AP180 is used in synaptic vesicle formation. It recruits clathrin to membranes and also promotes its polymerization. Epsin also recruits clathrin to membranes and promotes its polymerization, and can help deform the membrane, and thus clathrin-coated vesicles can bud. In a cell, a triskelion floating in the cytoplasm binds to an adaptor protein, linking one of its feet to the membrane at a time. The skelion will bind to other ones attached to the membrane to form a polyhedral lattice, skelion, which pulls the membrane into a bud. The skelion does not bind directly to the membrane, but binds to the adaptor proteins that recognize the molecules on the membrane surface.

Clathrin has another function aside from the coating of organelles. In non-dividing cells, the formation of clathrin-coated vesicles occurs continuously. Formation of clathrin-coated vesicles is shut down in cells undergoing mitosis. During mitosis, clathrin binds to the spindle apparatus. Clathrin aids in the congression of chromosomes by stabilizing fibres of the mitotic spindle. Clathrin is bound directly through the amino-terminal domain of the clathrin heavy chain. During mitosis the clathrin binds directly to the microtubules or microtubule-associated proteins. The stabilization of kinetochore fibres requires the trimetric structure of clathrin in order to strengthen the spindle fibres.[6]

Clathrin-mediated endocytosis (CME) regulates many cellular physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. It is believed that cellular invaders use the nutrient pathway to gain access to a cell's replicating mechanisms. Certain signalling molecules open the nutrients pathway. Two chemical compounds called Pitstop 1 and Pitstop 2, selective clathrin inhibitors, can interfere with the pathogenic activity, and thus protect the cells against invasion. These two compounds selectively block the endocytic ligand association with the clathrin terminal domain.[7]

See also[edit]

References[edit]

  1. ^ Pearse BM (April 1976). "Clathrin: a unique protein associated with intracellular transfer of membrane by coated vesicles". Proceedings of the National Academy of Sciences of the United States of America 73 (4): 1255–9. doi:10.1073/pnas.73.4.1255. PMC 430241. PMID 1063406. 
  2. ^ McMahon HT. "Clathrin and its interactions with AP180.". MRC Laboratory of Molecular Biology. Retrieved 2009-04-17. "micrographs of clathrin assembly" 
  3. ^ Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT (February 2001). "Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes". Science 291 (5506): 1051–5. doi:10.1126/science.291.5506.1051. PMID 11161218. 
  4. ^ Higgins MK, McMahon HT (May 2002). "Snap-shots of clathrin-mediated endocytosis". Trends in Biochemical Sciences 27 (5): 257–63. doi:10.1016/S0968-0004(02)02089-3. PMID 12076538. 
  5. ^ Royle SJ, Bright NA, Lagnado L (April 2005). "Clathrin is required for the function of the mitotic spindle". Nature 434 (7037): 1152–1157. doi:10.1038/nature03502. PMID 15858577. 
  6. ^ Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition|Cell, Volume 146, Issue 3, 471-484, 5 August 2011 Abstract

Further reading[edit]

External links[edit]