Clathrin

{{Infobox protein

| name = Clathrin light chain a

| bodyclass = collapsible collapsed

| image =

| width =

| caption =

| Symbol = CLTA

| AltSymbols =

| IUPHAR_id =

| ATC_prefix =

| ATC_suffix =

| ATC_supplemental =

| CAS_number =

| CAS_supplemental =

| DrugBank =

| EntrezGene = 1211

| HGNCid = HGNC:2090. CLTA.

| OMIM =

| PDB =

| RefSeq =

| UniProt = P09496

| ECnumber =

| Chromosome = 9

| Arm = q

| Band = 13

| LocusSupplementaryData =

}}

{{infobox protein

| Name = Clathrin light chain b

| bodyclass = collapsible collapsed

| caption =

| image =

| width =

| HGNCid = 2091

| Symbol = CLTB

| AltSymbols =

| EntrezGene = 1212

| OMIM = 118970

| RefSeq = NM_001834

| UniProt = P09497

| PDB =

| ECnumber =

| Chromosome = 5

| Arm = q

| Band = 35

| LocusSupplementaryData =

}}

{{infobox protein

| Name = Clathrin heavy chain 1

| bodyclass = collapsible collapsed

| caption =

| image =

| width =

| HGNCid = 2092

| Symbol = CLTC

| AltSymbols = CHC, CHC17, CLTCL2

| EntrezGene = 1213

| OMIM = 118955

| RefSeq = NM_004859

| UniProt = Q00610

| PDB =

| ECnumber =

| Chromosome = 17

| Arm = q

| Band = 23.1

| LocusSupplementaryData = -qter

}}

{{infobox protein

| Name = Clathrin heavy chain 2

| bodyclass = collapsible collapsed

| caption =

| image =

| width =

| HGNCid = 2093

| Symbol = CLTCL1

| AltSymbols = CLTCL

| EntrezGene = 8218

| OMIM = 601273

| RefSeq = NM_001835

| UniProt = P53675

| PDB =

| ECnumber =

| Chromosome = 22

| Arm = q

| Band = 11.21

| LocusSupplementaryData =

}}

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.{{cite journal |vauthors=Robinson MS |title=Forty Years of Clathrin-coated Vesicles |journal=Traffic |volume=16 |issue=12 |pages=1210–38 |date=December 2015 |pmid=26403691 |doi=10.1111/tra.12335 |url=|doi-access=free }}

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.{{cite journal |vauthors=Robinson MS |title=Forty Years of Clathrin-coated Vesicles |journal=Traffic |volume=16 |issue=12 |pages=1210–38 |date=December 2015 |pmid=26403691 |doi=10.1111/tra.12335 |url=|doi-access=free }}

{{multiple image

| align = center

| total_width = 440

| image1 = Clathrin cage viewed by croelectron microscopy.jpg

| caption1 = 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.

| image2 = Geometries of common clathrin assemblies.svg

| alt2 =

| link2 =

| thumbtime2 =

| caption2 = 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.{{cite journal |vauthors=Fotin A, Kirchhausen T, Grigorieff N, Harrison SC, Walz T, Cheng Y |title=Structure determination of clathrin coats to subnanometer resolution by single particle cryo-electron microscopy |journal=J Struct Biol |volume=156 |issue=3 |pages=453–60 |date=December 2006 |pmid=16908193 |pmc=2910098 |doi=10.1016/j.jsb.2006.07.001 |url=}}

Image:Itrafig2.jpg

Clathrin performs 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{{cite web| url =http://www.endocytosis.org/AP180/Clathrin.html| title =Clathrin and its interactions with AP180.| author =McMahon HT| publisher =MRC Laboratory of Molecular Biology| archive-url =https://web.archive.org/web/20090501052207/http://endocytosis.org/AP180/Clathrin.html| archive-date =2009-05-01| quote =micrographs of clathrin assembly| access-date =2009-04-17| url-status =dead}} and epsin.{{cite web| url =http://www.endocytosis.org/epsin/EM/MonolayerEMs.html| title =Epsin 1 EM gallery| author =McMahon HT| publisher =MRC Laboratory of Molecular Biology| archive-url =https://web.archive.org/web/20090102032308/http://www.endocytosis.org/epsin/EM/MonolayerEMs.html| archive-date =2009-01-02| quote =micrographs of vesicle budding| access-date =2009-04-17| url-status =dead}}{{cite journal | vauthors = Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT | title = Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes | journal = Science | volume = 291 | issue = 5506 | pages = 1051–1055 | date = February 2001 | pmid = 11161218 | doi = 10.1126/science.291.5506.1051 | url = http://www.endocytosis.org/epsin/EM/ford.pdf | url-status = dead | access-date = 2009-04-17 | author-link2 = Barbara Pearse | citeseerx = 10.1.1.407.6006 | bibcode = 2001Sci...291.1051F | archive-url = https://web.archive.org/web/20081121191304/http://www.endocytosis.org/epsin/EM/ford.pdf | archive-date = 2008-11-21 }}{{cite journal | vauthors = Higgins MK, McMahon HT | title = Snap-shots of clathrin-mediated endocytosis | journal = Trends in Biochemical Sciences | volume = 27 | issue = 5 | pages = 257–263 | date = May 2002 | pmid = 12076538 | doi = 10.1016/S0968-0004(02)02089-3 | url = http://www.endocytosis.org/epsin/EM/mcmahon.pdf | url-status = dead | access-date = 2009-04-17 | archive-url = https://web.archive.org/web/20081121220307/http://www.endocytosis.org/epsin/EM/mcmahon.pdf | archive-date = 2008-11-21 }} 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.{{cite journal | vauthors = Royle SJ, Bright NA, Lagnado L | title = Clathrin is required for the function of the mitotic spindle | journal = Nature | volume = 434 | issue = 7037 | pages = 1152–1157 | date = April 2005 | pmid = 15858577 | pmc = 3492753 | doi = 10.1038/nature03502 | bibcode = 2005Natur.434.1152R }}{{cite journal | vauthors = Hood FE, Williams SJ, Burgess SG, Richards MW, Roth D, Straube A, Pfuhl M, Bayliss R, Royle SJ | title = Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding | journal = The Journal of Cell Biology | volume = 202 | issue = 3 | pages = 463–478 | date = August 2013 | pmid = 23918938 | pmc = 3734082 | doi = 10.1083/jcb.201211127 }}{{cite journal | vauthors = Prichard KL, O'Brien NS, Murcia SR, Baker JR, McCluskey A | title = Role of Clathrin and Dynamin in Clathrin Mediated Endocytosis/Synaptic Vesicle Recycling and Implications in Neurological Diseases | journal = Frontiers in Cellular Neuroscience | volume = 15 | pages = 754110 | date = 2022-01-18 | pmid = 35115907 | pmc = 8805674 | doi = 10.3389/fncel.2021.754110 | doi-access = free }}

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 in vitro.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 [http://www.cell.com/abstract/S0092-8674%2811%2900667-2 Abstract] {{webarchive|url=https://web.archive.org/web/20120119233601/http://www.cell.com/abstract/S0092-8674(11)00667-2 |date=2012-01-19 }} However, the specificity of these compounds to block clathrin-mediated endocytosis has been questioned.{{cite journal | vauthors = Dutta D, Williamson CD, Cole NB, Donaldson JG | title = Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e45799 | date = Sep 2012 | pmid = 23029248 | pmc = 3448704 | doi = 10.1371/journal.pone.0045799 | doi-access = free | bibcode = 2012PLoSO...745799D }} In later studies, however, the specificity of Pitstop 2 was validated as being clathrin dependent.{{cite journal | vauthors = Robertson MJ, Horatscheck A, Sauer S, von Kleist L, Baker JR, Stahlschmidt W, Nazaré M, Whiting A, Chau N, Robinson PJ, Haucke V, McCluskey A | title = 5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors | journal = Organic & Biomolecular Chemistry | volume = 14 | issue = 47 | pages = 11266–11278 | date = November 2016 | pmid = 27853797 | doi = 10.1039/C6OB02308H }}

• Adaptin
• Cap formation
• Cell migration
• Dynamin

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{{Reflist|30em}}

{{refbegin | 30em}}

• {{cite journal | vauthors = Wakeham DE, Chen CY, Greene B, Hwang PK, Brodsky FM | title = Clathrin self-assembly involves coordinated weak interactions favorable for cellular regulation | journal = The EMBO Journal | volume = 22 | issue = 19 | pages = 4980–4990 | date = October 2003 | pmid = 14517237 | pmc = 204494 | doi = 10.1093/emboj/cdg511 }}
• {{cite journal | vauthors = Ford MG, Mills IG, Peter BJ, Vallis Y, Praefcke GJ, Evans PR, McMahon HT | title = Curvature of clathrin-coated pits driven by epsin | journal = Nature | volume = 419 | issue = 6905 | pages = 361–366 | date = September 2002 | pmid = 12353027 | doi = 10.1038/nature01020 | s2cid = 4372368 | bibcode = 2002Natur.419..361F }}
• {{cite journal | vauthors = Fotin A, Cheng Y, Sliz P, Grigorieff N, Harrison SC, Kirchhausen T, Walz T | title = Molecular model for a complete clathrin lattice from electron cryomicroscopy | journal = Nature | volume = 432 | issue = 7017 | pages = 573–579 | date = December 2004 | pmid = 15502812 | doi = 10.1038/nature03079 | s2cid = 4396282 | bibcode = 2004Natur.432..573F }}
• {{cite journal | vauthors = Mousavi SA, Malerød L, Berg T, Kjeken R | title = Clathrin-dependent endocytosis | journal = The Biochemical Journal | volume = 377 | issue = Pt 1 | pages = 1–16 | date = January 2004 | pmid = 14505490 | pmc = 1223844 | doi = 10.1042/BJ20031000 }}
• {{cite journal | vauthors = Smith CJ, Grigorieff N, Pearse BM | title = Clathrin coats at 21 A resolution: a cellular assembly designed to recycle multiple membrane receptors | journal = The EMBO Journal | volume = 17 | issue = 17 | pages = 4943–4953 | date = September 1998 | pmid = 9724631 | pmc = 1170823 | doi = 10.1093/emboj/17.17.4943 }} (Model of Clathrin assembly)
• {{cite journal | vauthors = Pérez-Gómez J, Moore I | title = Plant endocytosis: it is clathrin after all | journal = Current Biology | volume = 17 | issue = 6 | pages = R217–R219 | date = March 2007 | pmid = 17371763 | doi = 10.1016/j.cub.2007.01.045 | s2cid = 17680351 | doi-access = free | bibcode = 2007CBio...17.R217P }} (Review on involvement of clathrin in plant endocytosis)
• {{cite journal | vauthors = Royle SJ, Bright NA, Lagnado L | title = Clathrin is required for the function of the mitotic spindle | journal = Nature | volume = 434 | issue = 7037 | pages = 1152–1157 | date = April 2005 | pmid = 15858577 | pmc = 3492753 | doi = 10.1038/nature03502 | bibcode = 2005Natur.434.1152R }}
• {{cite journal | vauthors = Hood FE, Williams SJ, Burgess SG, Richards MW, Roth D, Straube A, Pfuhl M, Bayliss R, Royle SJ | title = Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding | journal = The Journal of Cell Biology | volume = 202 | issue = 3 | pages = 463–478 | date = August 2013 | pmid = 23918938 | pmc = 3734082 | doi = 10.1083/jcb.201211127 }}
• {{cite journal | vauthors = Knuehl C, Chen CY, Manalo V, Hwang PK, Ota N, Brodsky FM | title = Novel binding sites on clathrin and adaptors regulate distinct aspects of coat assembly | journal = Traffic | volume = 7 | issue = 12 | pages = 1688–1700 | date = December 2006 | pmid = 17052248 | doi = 10.1111/j.1600-0854.2006.00499.x | s2cid = 19087208 | doi-access = free }}
• {{cite journal | vauthors = Edeling MA, Smith C, Owen D | title = Life of a clathrin coat: insights from clathrin and AP structures | journal = Nature Reviews. Molecular Cell Biology | volume = 7 | issue = 1 | pages = 32–44 | date = January 2006 | pmid = 16493411 | doi = 10.1038/nrm1786 | s2cid = 19393938 }}
• {{cite journal | vauthors = Dutta D, Williamson CD, Cole NB, Donaldson JG | title = Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis | journal = PLOS ONE | volume = 7 | issue = 9 | pages = e45799 | date = Sep 2012 | pmid = 23029248 | pmc = 3448704 | doi = 10.1371/journal.pone.0045799 | doi-access = free | bibcode = 2012PLoSO...745799D }}

{{refend}}

• [http://www.mechanobio.info/topics/cellular-organization/go-0072583 MBInfo - Clathrin Mediated Endocytosis]
• {{ELM|LIG_Clathr_ClatBox_1}}
• {{ELM|LIG_Clathr_ClatBox_2}}
• [http://www-als.lbl.gov/als/science/sci_archive/clathrin.html Clathrin structure]
• [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.114 Membrane Dynamics]
• [http://cellimages.ascb.org/images/7760 Clathrin Dynamics]{{Dead link|date=February 2022 |bot=InternetArchiveBot |fix-attempted=yes }} ASCB Image & Video Library

{{Vesicular transport proteins}}

Category:Proteins

Category:Cell biology

Category:Peripheral membrane proteins