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<Structure load='3lvg' size='350' frame='true' align='right' caption='Clathrin' scene='Insert optional scene name here' />

'''Clathrin''' originates from the Latin word clāthrātus, meaning “to provide with a lattice”.<ref> Clathrin. (2015). ''Oxford University Press''. Retrieved from http://www.oxforddictionaries.com/us/definition/american_english/clathrin.</ref> Clathrin is a protein involved in receptor-mediated endocytosis.<ref name="harrison"> Harrison, S. C., Kirchhausen, T., & Owen, D. (2014). Molecular structure, function, and dynamics of clathrin-mediated membrane traffic. ''Cold Spring Harbor Perspectives in Biology.'' [http://dx.doi.org/10.1101/cshperspect.a016725 doi: 10.1101/cshperspect.a016725]</ref> The protein was discovered by Barbara Pearse, a biological scientist, in 1975.<ref name="pearse">PMID: 1063406</ref> Clathrin is a protein resembling a triskelion shape and is composed of three heavy chains and three light chains which come together to form a polyhedral lattice similar to a cage.<ref name="harrison" /> The three heavy chains resemble three legs protruding from a center point. Some of the major functions of clathrin include lysosomal targeting, receptor-mediated endocytosis, and organelle biogenesis from the trans-Golgi network.<ref name="wakeham">Wakeham, D. E., et al. (2003). Clathrin self-assembly involves coordinated weak interactions favorable for cellular recognition. ''The Embo Journal.'' [http://dx.doi.org/10.1093/emboj/cdg511 doi:  10.1093/emboj/cdg511]</ref> The polyhedral lattice shape of clathrin largely determines its functionality, in that there are many binding sites for proteins on the heavy chains of the lattice as well.<ref name="ungewickell">Ungewickell, E., & Brandon, D. (1981). Assembly units of clathrin coats. ''Nature, 289'', 420-42. [http://dx.doi.org/10.1038/289420a0 doi: 10.1038/289420a0]</ref>

== Structure == 
===Individual Molecule===

An individual clathrin molecule is composed of <scene name='71/716515/Chains/1'>three heavy chains, which each have a light chain attached to them</scene> This structure is often referred to as a triskelion shape.<ref name="harrison" /> The heavy chains of clathrin are made of an amino-terminal, a beta-propellor domain which contain multiple repeats of the WD40 binding motif, alpha-helical zig-zags close to 30 amino acids in length, a lengthened alpha-helix where the threefold contacts, and a <scene name='71/716515/Carboxy_terminals/2'>carboxy terminal</scene><ref name="harrison" /> The aforementioned zig-zags are what create the “leg” looking structure of the triskelion.<ref name="harrison" /> A segment of the heavy chain is designed with the purpose of attaching to the light chain.<ref name="harrison" /> The heavy chain and light chain bind through one long alpha helix towards the center of the protein.<ref name="harrison" />

[[Image:LatticeStructure.png |frame| '''Figure 1'''. a) Clathrin monomer with labeled heavy and light chains b) Clathrin monomers forming a basic lattice structure.<ref name="pearse">PMID: 1063406</ref> Clathrin is made of individual triskelion components that come together to form the cage-like structure of clathrin.<ref name="crowther" /> Each vertex is composed of a triskelion leg.<ref name="crowther" /> Although there are various packing models for clathrin cage assembly, the overall theme is multiple triskelions coming together to form the cage like structure.<ref name="crowther" />]]

===Lattice===

Individual clathrin molecules can assemble into cage-like structures. When individual clathrin molecules come together, a lattice is formed where each lattice point is associated with the center of a triskelion (from the Greek word meaning “a three legged structure”) (Figure 1).<ref name="harrison" /> According to Crowther, R.A., clathrin vesicles are constructed from twelve pentagonal units plus a number of hexagonal units, with the number of hexagons increasing for larger clathrin coats.<ref name="crowther">PMID: 7328122 </ref> The term “cage” can be used to refer to empty shells composed only of clathrin while the term “coat” refers to clathrin in addition to associated proteins and vesicles.<ref name="crowther" /> Clathrin lattices are formed under optimal conditions of physiological pH (6.0-6.5) and in the presence of Calcium or Magnesium ions.<ref name="crowther" /> Various packing models have been investigated as to how the individual triskelion legs assemble into clathrin cages.<ref name="crowther" /> As mentioned above, the center of the triskelion legs occurs at each vertex of the cage, meaning pentagons, heptagons, and hexagons can be formed.<ref name="crowther" /> In the individual triskelion legs, the bend in the leg is 160 Angstroms from the vertex, giving rise to two models of packing: simple side-by-side packing or a cross-over type of packing (Figure 2).<ref name="crowther" /> Cross-over packing occurs when a hexamer of triskelions is formed with crossing over of the leg portions of the triskelions.<ref name="crowther" /> Rather than involving crossing over, simple packing refers to side by side packing of the leg portions of the triskelions (Figure 2).<ref name="crowther" /> 

[[Image:LaatticeStructure2.png |frame| '''Figure 2'''. Models of the various packing models of triskelion components of clathrin.<ref name="crowther" /> Each vertex of the polygon is made of a triskelion and the legs of the triskelion run along the edges. (a) Simple side-by-side packing model of the legs in which there is no overlap and a hexamer is formed. (b) Model of cross-over packing of the triskelion legs forming a hexamer and (c) Similar model as (b) except a pentamer is formed by the triskelions with crossing over of the leg portions.<ref name="crowther" />]]

== Function ==

===Endocytosis===

There are various endocytic mechanisms by which eukaryotic cells bring proteins and lipids into the cell, however clathrin-mediated endocytosis is known to be the most informative pathway to date.<ref name="mcpherson"> McPherson, P. S., Ritter, B., & Wendland, B. Clathrin-Mediated Endocytosis. (2009).  Clathrin-Mediated Endocytosis. In Trafficking Inside Cells: Pathways, Mechanisms, and Regulation (Section II). [http://dx.doi.org/10.1007/978-0-387-93877-6_9 doi: 10.1007/978-0-387-93877-6_9]</ref> Other portals for endocytic entry include phagocytosis and macropinocytosis.<ref name="mcpherson"> McPherson, P. S., Ritter, B., & Wendland, B. Clathrin-Mediated Endocytosis. (2009).  Clathrin-Mediated Endocytosis. In Trafficking Inside Cells: Pathways, Mechanisms, and Regulation (Section II). [http://dx.doi.org/10.1007/978-0-387-93877-6_9 doi: 10.1007/978-0-387-93877-6_9]</ref> Endocytic events are initiated through the activity of the clathrin coat and adaptor proteins that select the “cargo” that will be carried into the cell in vesicles.<ref name ="johnson"> Johnson, G. T., & Goodsell, D. (2007). Molecule of the Month: Clathrin. [http://dx.doi.org/10.2210/rcsb_pdb/mom_2007_4 doi: 10.2210/rcsb_pdb/mom_2007_4]</ref> At least twenty clathrin adaptors have been identified, and they all recognize and bind to membrane proteins or phospholipids that are specific for a certain organelle.<ref name ="johnson" /> The formation of most cellular vesicles are facilitated by these coat-proteins like clathrin.<ref name ="johnson" /> Cells endocytose vesicles from the plasma membrane to perform housekeeping tasks such as taking up nutrients, importing signaling receptors, mediating immune responses, cleaning up cell debris, or providing a pathway for pathogens or toxins.<ref name ="johnson" /> Clathrin uses two main pathways for endocytosis: the canonical pathway and noncanonical pathway. The canonical clathrin pathway is referred to as the clathrin coated pits and the coated vesicles of endocytosis, whereas the noncanonical clathrin pathway is related to the clathrin-actin assembles of phagocytotic processes.<ref name="harrison" />


===The Canonical Pathway===

Classical endocytosis involving clathrin-coated pits and clathrin-coated vesicles is referred to as the canonical clathrin pathway (Figure 3).<ref name="harrison" /> Canonical clathrin-dependent pathways involve the uptake of transferrin (Tf) by transferrin receptor (TfR) and the uptake of LDL by LDL receptors (LDLR).<ref name="harrison" /> Early studies showed that LDL epidermal growth factor (Tf) bound to their specific receptors could be endocytosed within the same vesicle.<ref name="harrison" /> The receptors for these molecules are composed of tails on their cytoplasmic side that contain sequences, which determine cargo sorting and also signal for clathrin to bind.<ref name="harrison" /> Clathrin then coats these vesicles and endocytosis occurs.<ref name="harrison" /> Other pathways, such as reuptake of neurotransmitters into the synaptic cleft, are seen to have similar mechanisms to canonical clathrin pathways.<ref name="harrison" />

[[Image:Endocytosis.gif |frame| '''Figure 3'''. Formation and dissociation of a canonical, endocytitic clathrin-coated pit.<ref name="harrison" />]]


===The Noncanonical Pathway===

The noncanonical clathrin pathway refers to clathrin-actin assemblies, which form phagocytotic vesicles in response to invading bacterium.<ref name="harrison" /> Pathogen invasion into nonphagocytic cells result in the recruitment of clathrin.<ref name="harrison" /> These pathogens invade the cell through a process called the “zippering” mechanism, in which actin filaments are utilized to surround the pathogens with the host-cell membrane.<ref name="harrison" /> Actin recruitment requires the formation of clathrin patches and thus the clathrin-assembly forms.<ref name="harrison" /> Actin is not usually needed in classical endocytosis, but it is required when the size of the cargo in the forming vesicle is too large for the vesicle to close.<ref name="harrison" /> This association between actin and clathrin is unique to this pathway and distinguishes the noncanonical pathway from the canonical pathway.<ref name="harrison" />


== References ==
<references/>