Clathrin

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Clathrin heavy N-terminal propeller repeat
PDB 1c9l EBI.jpg
Clathrin terminal domain
Identifiers
SymbolClathrin_propel
Pfam PF01394
Pfam clan CL0020
InterPro IPR022365
SCOP2 1bpo / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Clathrin heavy-chain linker
PDB 1b89 EBI.jpg
clathrin heavy chain proximal repeat (linker)
Identifiers
SymbolClathrin-link
Pfam PF09268
Pfam clan CL0020
InterPro IPR015348
SCOP2 1b89 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
CHCR/VPS 7-fold repeat
Identifiers
SymbolClathrin_propel
Pfam PF00637
Pfam clan CL0020
InterPro IPR000547
SMART SM00299
PROSITE PS50236
CATH 1b89
SCOP2 1b89 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Clathrin light chain
Identifiers
SymbolClathrin_lg_ch
Pfam PF01086
InterPro IPR000996
PROSITE PDOC00196
SCOP2 3iyv / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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]

Contents

Structure

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]

Clathrin cage viewed by croelectron microscopy.jpg
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.
Geometries of common clathrin assemblies.svg
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. Itrafig2.jpg
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

Related Research Articles

<span class="mw-page-title-main">Endocytosis</span> Cellular process

Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested materials. Endocytosis includes pinocytosis and phagocytosis. It is a form of active transport.

<span class="mw-page-title-main">COPI</span> Protein complex

COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum (ER), where they were originally synthesized, and between Golgi compartments. This type of transport is retrograde transport, in contrast to the anterograde transport associated with the COPII protein. The name "COPI" refers to the specific coat protein complex that initiates the budding process on the cis-Golgi membrane. The coat consists of large protein subcomplexes that are made of seven different protein subunits, namely α, β, β', γ, δ, ε and ζ.

<span class="mw-page-title-main">Receptor-mediated endocytosis</span> Process by which cells absorb materials

Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process.

<span class="mw-page-title-main">Vesicular transport adaptor protein</span>

Vesicular transport adaptor proteins are proteins involved in forming complexes that function in the trafficking of molecules from one subcellular location to another. These complexes concentrate the correct cargo molecules in vesicles that bud or extrude off of one organelle and travel to another location, where the cargo is delivered. While some of the details of how these adaptor proteins achieve their trafficking specificity has been worked out, there is still much to be learned.

Barbara Mary Frances Pearse FRS is a British biological scientist. She works at the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom.

AP180 is a protein that plays an important role in clathrin-mediated endocytosis of synaptic vesicles. It is capable of simultaneously binding both membrane lipids and clathrin and is therefore thought to recruit clathrin to the membrane of newly invaginating vesicles. In Drosophila melanogaster, deletion of the AP180 homologue, leads to enlarged but much fewer vesicles and an overall decrease in transmitter release. In D. melanogaster it was also shown that AP180 is also required for either recycling vesicle proteins and/or maintaining the distribution of both vesicle and synaptic proteins in the nerve terminal. A ubiquitous form of the protein in mammals, CALM, is named after its association with myeloid and lymphoid leukemias where some translocations map to this gene. The C-terminus of AP180 is a powerful and specific inhibitor of clathrin-mediated endocytosis.

<span class="mw-page-title-main">ANTH domain</span>

The ANTH domain is a membrane binding domain that shows weak specificity for PtdIns(4,5)P2. It was found in AP180 endocytotic accessory protein that has been implicated in the formation of clathrin-coated pits. The domain is involved in phosphatidylinositol 4,5-bisphosphate binding and is a universal adaptor for nucleation of clathrin coats.

<span class="mw-page-title-main">ENTH domain</span> InterPro Domain

The epsin N-terminal homology (ENTH) domain is a structural domain that is found in proteins involved in endocytosis and cytoskeletal machinery.

<span class="mw-page-title-main">Epsin</span>

Epsins are a family of highly conserved membrane proteins that are important in creating membrane curvature. Epsins contribute to membrane deformations like endocytosis, and block vesicle formation during mitosis.

<span class="mw-page-title-main">Amphiphysin</span> Protein-coding gene in the species Homo sapiens

Amphiphysin is a protein that in humans is encoded by the AMPH gene.

<span class="mw-page-title-main">AP2 adaptor complex</span>

The AP2 adaptor complex is a multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis. It is a stable complex of four adaptins which give rise to a structure that has a core domain and two appendage domains attached to the core domain by polypeptide linkers. These appendage domains are sometimes called 'ears'. The core domain binds to the membrane and to cargo destined for internalisation. The alpha and beta appendage domains bind to accessory proteins and to clathrin. Their interactions allow the temporal and spatial regulation of the assembly of clathrin-coated vesicles and their endocytosis.

<span class="mw-page-title-main">Adaptor-related protein complex 2, alpha 1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit alpha-1 is a protein that in humans is encoded by the AP2A1 gene.

<span class="mw-page-title-main">AP1M1</span> Protein-coding gene in the species Homo sapiens

AP-1 complex subunit mu-1 is a protein that in humans is encoded by the AP1M1 gene.

<span class="mw-page-title-main">AP1B1</span> Protein-coding gene in the species Homo sapiens

AP-1 complex subunit beta-1 is a protein that in humans is encoded by the AP1B1 gene.

<span class="mw-page-title-main">AP2B1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit beta is a protein that in humans is encoded by the AP2B1 gene.

<span class="mw-page-title-main">AP1S1</span> Protein-coding gene in the species Homo sapiens

AP-1 complex subunit sigma-1A is a protein that in humans is encoded by the AP1S1 gene.

<span class="mw-page-title-main">EPN1</span> Protein-coding gene in the species Homo sapiens

Epsin-1 is a protein that in humans is encoded by the EPN1 gene.

<span class="mw-page-title-main">AP2S1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit sigma is a protein that in humans is encoded by the AP2S1 gene.

Clathrin adaptor proteins, also known as adaptins, are vesicular transport adaptor proteins associated with clathrin. These proteins are synthesized in the ribosomes, processed in the endoplasmic reticulum and transported from the Golgi apparatus to the trans-Golgi network, and from there via small carrier vesicles to their final destination compartment. The association between adaptins and clathrin are important for vesicular cargo selection and transporting. Clathrin coats contain both clathrin and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. Therefore, adaptor proteins are responsible for the recruitment of cargo molecules into a growing clathrin-coated pits. The two major types of clathrin adaptor complexes are the heterotetrameric vesicular transport adaptor proteins (AP1-5), and the monomeric GGA adaptors. Adaptins are distantly related to the other main type of vesicular transport proteins, the coatomer subunits, sharing between 16% and 26% of their amino acid sequence.

<span class="mw-page-title-main">Beta2-adaptin C-terminal domain</span>

The C-terminal domain ofBeta2-adaptin is a protein domain is involved in cell trafficking by aiding import and export of substances in and out of the cell.

References

  1. 1 2 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): 1255–1259. Bibcode:1976PNAS...73.1255P. doi: 10.1073/pnas.73.4.1255 . PMC   430241 . PMID   1063406.
  2. ↑ "clathrate, adjective". Merriam-Webster. Retrieved 29 November 2023.
  3. ↑ Pearse BM (September 1987). "Clathrin and coated vesicles". EMBO J. 6 (9): 2507–12. doi:10.1002/j.1460-2075.1987.tb02536.x. PMC   553666 . PMID   2890519.
  4. ↑ "InterPro". Archived from the original on 2016-01-16. Retrieved 2015-10-07.
  5. 1 2 Robinson MS (December 2015). "Forty Years of Clathrin-coated Vesicles". Traffic. 16 (12): 1210–38. doi: 10.1111/tra.12335 . PMID   26403691.
  6. ↑ Fotin A, Kirchhausen T, Grigorieff N, Harrison SC, Walz T, Cheng Y (December 2006). "Structure determination of clathrin coats to subnanometer resolution by single particle cryo-electron microscopy". J Struct Biol. 156 (3): 453–60. doi:10.1016/j.jsb.2006.07.001. PMC   2910098 . PMID   16908193.
  7. ↑ McMahon HT. "Clathrin and its interactions with AP180". MRC Laboratory of Molecular Biology. Archived from the original on 2009-05-01. Retrieved 2009-04-17. micrographs of clathrin assembly
  8. ↑ Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, et al. (February 2001). "Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes" (PDF). Science. 291 (5506): 1051–1055. Bibcode:2001Sci...291.1051F. CiteSeerX   10.1.1.407.6006 . doi:10.1126/science.291.5506.1051. PMID   11161218. Archived from the original (PDF) on 2008-11-21. Retrieved 2009-04-17.
  9. ↑ Higgins MK, McMahon HT (May 2002). "Snap-shots of clathrin-mediated endocytosis" (PDF). Trends in Biochemical Sciences. 27 (5): 257–263. doi:10.1016/S0968-0004(02)02089-3. PMID   12076538. Archived from the original (PDF) on 2008-11-21. Retrieved 2009-04-17.
  10. ↑ Royle SJ, Bright NA, Lagnado L (April 2005). "Clathrin is required for the function of the mitotic spindle". Nature. 434 (7037): 1152–1157. Bibcode:2005Natur.434.1152R. doi:10.1038/nature03502. PMC   3492753 . PMID   15858577.
  11. ↑ Hood FE, Williams SJ, Burgess SG, Richards MW, Roth D, Straube A, et al. (August 2013). "Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding". The Journal of Cell Biology. 202 (3): 463–478. doi:10.1083/jcb.201211127. PMC   3734082 . PMID   23918938.
  12. ↑ Prichard KL, O'Brien NS, Murcia SR, Baker JR, McCluskey A (2022-01-18). "Role of Clathrin and Dynamin in Clathrin Mediated Endocytosis/Synaptic Vesicle Recycling and Implications in Neurological Diseases". Frontiers in Cellular Neuroscience. 15: 754110. doi: 10.3389/fncel.2021.754110 . PMC   8805674 . 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 Archived 2012-01-19 at the Wayback Machine
  14. ↑ Dutta D, Williamson CD, Cole NB, Donaldson JG (Sep 2012). "Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis". PLOS ONE. 7 (9): e45799. Bibcode:2012PLoSO...745799D. doi: 10.1371/journal.pone.0045799 . PMC   3448704 . PMID   23029248.
  15. ↑ Robertson MJ, Horatscheck A, Sauer S, von Kleist L, Baker JR, Stahlschmidt W, et al. (November 2016). "5-Aryl-2-(naphtha-1-yl)sulfonamido-thiazol-4(5H)-ones as clathrin inhibitors". Organic & Biomolecular Chemistry. 14 (47): 11266–11278. doi:10.1039/C6OB02308H. PMID   27853797.

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