Biology:Clathrin

From HandWiki
Short description: Protein playing a major role in the formation of coated vesicles
Clathrin heavy N-terminal propeller repeat
PDB 1c9l EBI.jpg
Clathrin terminal domain
Identifiers
SymbolClathrin_propel
PfamPF01394
Pfam clanCL0020
InterProIPR022365
SCOP21bpo / SCOPe / SUPFAM
Clathrin heavy-chain linker
PDB 1b89 EBI.jpg
clathrin heavy chain proximal repeat (linker)
Identifiers
SymbolClathrin-link
PfamPF09268
Pfam clanCL0020
InterProIPR015348
SCOP21b89 / SCOPe / SUPFAM
CHCR/VPS 7-fold repeat
Identifiers
SymbolClathrin_propel
PfamPF00637
Pfam clanCL0020
InterProIPR000547
SMARTSM00299
PROSITEPS50236
CATH1b89
SCOP21b89 / SCOPe / SUPFAM
Clathrin light chain
Identifiers
SymbolClathrin_lg_ch
PfamPF01086
InterProIPR000996
PROSITEPDOC00196
SCOP23iyv / SCOPe / SUPFAM

Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated by Barbara Pearse in 1976.[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. The protein's name refers to this lattice structure, deriving from Latin clathri meaning lattice.[2] Barbara Pearse named the protein clathrin at the suggestion of Graeme Mitchison, selecting it from three possible options.[3] Coat-proteins, like clathrin, are used to build small vesicles in order to transport molecules within cells. The endocytosis and exocytosis of vesicles allows cells to communicate, 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. The endocytic pathway can be hijacked by viruses and other pathogens in order to gain entry to the cell during infection.[4]

Structure

Clathrin light chain a
Identifiers
SymbolCLTA
NCBI gene1211
HGNCCLTA. HGNC:2090. CLTA.
UniProtP09496
Other data
LocusChr. 9 q13
Clathrin light chain b
Identifiers
SymbolCLTB
NCBI gene1212
HGNC2091
OMIM118970
RefSeqNM_001834
UniProtP09497
Other data
LocusChr. 5 q35
Clathrin heavy chain 1
Identifiers
SymbolCLTC
Alt. symbolsCHC, CHC17, CLTCL2
NCBI gene1213
HGNC2092
OMIM118955
RefSeqNM_004859
UniProtQ00610
Other data
LocusChr. 17 q23.1-qter
Clathrin heavy chain 2
Identifiers
SymbolCLTCL1
Alt. symbolsCLTCL
NCBI gene8218
HGNC2093
OMIM601273
RefSeqNM_001835
UniProtP53675
Other data
LocusChr. 22 q11.21

The clathrin triskelion is composed of three clathrin heavy chains interacting at their C-termini, each ~190 kDa heavy chain has a ~25 kDa light chain tightly bound to it. 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. There are two forms of clathrin light chains, designated a and b. The main clathrin heavy chain, located on chromosome 17 in humans, is found in all cells. A second clathrin heavy chain gene, on chromosome 22, is expressed in muscle.[5]

Clathrin heavy chain is often described as a leg, with subdomains, representing the foot (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. The β-propeller at the 'foot' of clathrin contains multiple binding sites for interaction with other proteins.[5]

A clathrin cage with a single triskelion highlighted in blue. CryoEM map EMD_5119 was rendered in UCSF Chimera and one clathrin triskelion was highlighted.
Each cage has 12 pentagons. Mini-coat (left) has 4 hexagons and tetrahedral symmetry as in a truncated triakis tetrahedron. Hexagonal barrel (middle) has 8 hexagons and D6 symmetry. Soccer ball (right) has 20 hexagons and icosahedral symmetry as in a truncated icosahedron.

When triskelia assemble together in solution, they can interact with enough flexibility to form 6-sided rings (hexagons) that yield a flat lattice, or 5-sided rings (pentagons) that are necessary for curved lattice formation. When many triskelions connect, they can form a basket-like structure. The structure shown, is built of 36 triskelia, one of which is shown in blue. Another common assembly is a truncated icosahedron. To enclose a vesicle, exactly 12 pentagons must be present in the lattice.

In a cell, clathrin triskelion in the cytoplasm binds to an adaptor protein that has bound membrane, linking one of its three feet to the membrane at a time. Clathrin cannot bind to membrane or cargo directly and instead uses adaptor proteins to do this. 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.[6]

Function

Mechanism of clathrin-mediated endocytosis.
Mechanism of clathrin-mediated endocytosis.

Clathrin performs critical roles in shaping rounded vesicles in the cytoplasm for intracellular trafficking. Clathrin-coated vesicles (CCVs) 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[7] and epsin.[8][9][10] 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 triskelion foot will bind to other ones attached to the membrane to form a polyhedral lattice, triskelion foot, which pulls the membrane into a bud. The foot 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, in complex with two other proteins: TACC3 and ch-TOG/CKAP5. Clathrin aids in the congression of chromosomes by stabilizing kinetochore fibers of the mitotic spindle. The amino-terminal domain of the clathrin heavy chain and the TACC domain of TACC3 make the microtubule binding surface for TACC3/ch-TOG/clathrin to bind to the mitotic spindle. The stabilization of kinetochore fibers requires the trimeric structure of clathrin in order to crosslink microtubules.[11][12][13]

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.[1] 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 in vitro.[14] However, the specificity of these compounds to block clathrin-mediated endocytosis has been questioned.[15] In later studies, however, the specificity of Pitstop 2 was validated as being clathrin dependent.[16]

See also

References

  1. ↑ 1.0 1.1 "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): 1255–1259. April 1976. doi:10.1073/pnas.73.4.1255. PMID 1063406. Bibcode: 1976PNAS...73.1255P. 
  2. ↑ "clathrate, adjective". Merriam-Webster. https://www.merriam-webster.com/dictionary/clathrate. 
  3. ↑ "Clathrin and coated vesicles". EMBO J 6 (9): 2507–12. September 1987. doi:10.1002/j.1460-2075.1987.tb02536.x. PMID 2890519. 
  4. ↑ "InterPro". https://www.ebi.ac.uk/interpro/potm/2007_4/Page1.htm. 
  5. ↑ 5.0 5.1 "Forty Years of Clathrin-coated Vesicles". Traffic 16 (12): 1210–38. December 2015. doi:10.1111/tra.12335. PMID 26403691. 
  6. ↑ "Structure determination of clathrin coats to subnanometer resolution by single particle cryo-electron microscopy". J Struct Biol 156 (3): 453–60. December 2006. doi:10.1016/j.jsb.2006.07.001. PMID 16908193. 
  7. ↑ McMahon HT. "Clathrin and its interactions with AP180.". MRC Laboratory of Molecular Biology. http://www.endocytosis.org/AP180/Clathrin.html. "micrographs of clathrin assembly" 
  8. ↑ "Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes". Science 291 (5506): 1051–1055. February 2001. doi:10.1126/science.291.5506.1051. PMID 11161218. Bibcode: 2001Sci...291.1051F. http://www.endocytosis.org/epsin/EM/ford.pdf. Retrieved 2009-04-17. 
  9. ↑ "Snap-shots of clathrin-mediated endocytosis". Trends in Biochemical Sciences 27 (5): 257–263. May 2002. doi:10.1016/S0968-0004(02)02089-3. PMID 12076538. http://www.endocytosis.org/epsin/EM/mcmahon.pdf. Retrieved 2009-04-17. 
  10. ↑ "Clathrin is required for the function of the mitotic spindle". Nature 434 (7037): 1152–1157. April 2005. doi:10.1038/nature03502. PMID 15858577. Bibcode: 2005Natur.434.1152R. 
  11. ↑ "Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding". The Journal of Cell Biology 202 (3): 463–478. August 2013. doi:10.1083/jcb.201211127. PMID 23918938. 
  12. ↑ "Role of Clathrin and Dynamin in Clathrin Mediated Endocytosis/Synaptic Vesicle Recycling and Implications in Neurological Diseases". Frontiers in Cellular Neuroscience 15: 754110. 2022-01-18. doi:10.3389/fncel.2021.754110. PMID 35115907. 
  13. ↑ 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
  14. ↑ "Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis". PLOS ONE 7 (9): e45799. Sep 2012. doi:10.1371/journal.pone.0045799. PMID 23029248. Bibcode: 2012PLoSO...745799D. 
  15. ↑ "5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors". Organic & Biomolecular Chemistry 14 (47): 11266–11278. November 2016. doi:10.1039/C6OB02308H. PMID 27853797. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Clathrin&oldid=3573840"