Clathrin plays an important role in vesicular transport in all compartmentalised cells from yeast to humans. Clathrin is a protein with a highly extended shape that can assemble into polyhedral structures. Formation of transport vesicles during many of the membrane‐trafficking processes in eukaryotic cells involves the polymerisation of clathrin into such polyhedral shells around the nascent vesicles. The recruitment and polymerisation of clathrin to specific regions on cell membranes where vesicular cargo is concentrated is a highly regulated process that involves both clathrin adaptor proteins and membrane phosphoinositides. Once a vesicle enveloped by clathrin is released from a membrane, another regulated process mediated by the ATP (adenosine triphosphate)‐hydrolysing Hsc70 chaperone depolymerises the clathrin, resulting in formation of mature transport vesicles. The depolymerised clathrin remains associated with Hsc70 to prevent its aberrant polymerisation.

Key Concepts

  • Clathrin is a major mediator of vesicular transport in all compartmentalised cells, from yeast to humans.
  • Clathrin has the property of self‐assembly.
  • When clathrin assembly takes place on a membrane, it contributes to the mechanical deformation of the membrane.
  • Clathrin is recruited to membranes by interactions with adaptor proteins.
  • Adaptor proteins are recruited to membranes by interactions with cargo proteins and phosphoinositides.
  • Intrinsic disorder in clathrin assembly proteins is important for clathrin lattice formation at membranes.
  • Release of a clathrin‐coated vesicle from a membrane is driven by the GTPase dynamin.
  • The uncoating of a clathrin‐coated vesicle is catalysed by the ATPase Hsc70.
  • Hsc70 mediates uncoating by a collision pressure mechanism, whereby collisions between the walls of the clathrin coat and Hsc70s drive the coat apart.
  • Hsc70 chaperones clathrin triskelia to prevent aberrant polymerisation.

Keywords: clathrin; coated vesicle; AP180; AP‐2; auxilin; Hsc70; adaptor protein; chaperone; endocytosis; vesicle trafficking

Figure 1. Clathrin triskelia and coat structure. (a) Model of a clathrin coat [1XI4.pdb (Fotin et al., )] with its interior coloured blue, cyan and green, and its exterior surface coloured yellow, orange and red. The coat is ∼70 nm in diameter that comprised 36 triskelia arranged with pentagonal and hexagonal symmetry via interactions between their legs. The view is centred on a single triskelion with its CHCs (clathrin heavy chains) and CLCs (clathrin light chains) coloured magenta and dark grey, respectively. (b) Model of a single triskelion isolated from the basket shown in (a). The three CHCs that comprise the triskelion are coloured cyan, red and yellow while the CLCs associated with the CHCs are in magenta. The different segments of the CHC, extending from the terminal domain (TD) to the carboxy terminal hub are indicated. (c) Reorientation of the triskelion shown in (b) by a 90° rotation as indicated. The helical tripod, which projects into the interior of the assembled basket, is visible. Flexible tails (not shown) emerging from these helices contain the binding site for Hsc70, which uses ATP (adenosine triphosphate) to disassemble the basket (Rapoport et al., ). Also shown are two sets of auxilin molecules [1XI5.pdb (Fotin et al., )]. In purple are the cis‐auxilins, that is those which bind directly to the illustrated triskelion but which are probably too far from the tripod to load Hsc70. In blue are the trans‐auxilins, which are bound to the neighbouring triskelia but are placed closed enough to the tripod to load Hsc70. Shown in grey is a fragment of one of these neighbouring triskelia, which illustrates how they achieve appropriate positioning of the auxilins so that Hsc70 loading is directed to clathrin coats and not free triskelia.
Figure 2. The role of clathrin in synaptic vesicle recycling: (1) Communication between neurons across synapses involves fusion of synaptic vesicles with the presynaptic plasma membrane and release of neurotransmitter (red). (2) Synaptic vesicle proteins (grey bars) then need to be retrieved to replenish the pool of synaptic vesicles. The first step in this is the binding of assembly proteins to membrane PI(4,5)P2, as well as to the sorting signals on the synaptic vesicle proteins. (3) The assembly proteins then recruit and facilitate the polymerisation of clathrin on the membrane, leading to membrane invagination to form a clathrin‐coated pit (CCP). (4) Dynamin (green) oligomerises to form a ring around the neck of the nascent vesicle and carries out the final scission step that releases the clathrin‐coated vesicle (CCV) from the membrane. (5) Auxilin then binds to the clathrin and recruits ATP bound Hsc70 (orange). (6) Hsc70 disassembles the coat, releasing triskelia that remain associated with (chaperoned by) Hsc70. (7) When clathrin is required for endocytosis an Hsc70 nucleotide exchange factor (the NEF Hsp110) releases the Hsc70 from clathrin.
Figure 3. Closed and open conformations of the AP‐2 clathrin adaptor. (a) Ribbon model of the closed form [4uqi.pdb (Kelly et al., )] with the α, β2, μ2 and σ2 subunits in blue, cyan, green and red, respectively. Highlighted in space‐filling representation, and labelled with text of the same colour, are the acidic dileucine motif binding element (‘DiLeu’; red), the YXXΦ binding element (‘YXXΦ’; green), the clathrin binding site (‘C‐box’; magenta) and the inositol phosphate binding sites on the α‐ (α‐IP; grey) and μ2‐ (μ‐IP; grey) subunits. In the closed conformation, the clathrin‐box, dileucine and YXXF binding elements are wholly or partially occluded, but the IP sites are accessible and AP‐2 can bind IPs. (b) The open form of AP‐2 [2xa7.pdb (Jackson et al., )] with colouring and labelling as in (a). Upon membrane binding a large rotation of the C‐terminal domain of μ2 and movements in the β‐subunit expose the two cargo binding sites and place them in a coplanar arrangement with the two IP binding sites so that all sites can bind their membrane target simultaneously (in this view, the membrane would be above the AP‐2). This rotation also exposes the clathrin binding element which is not visible in this structure because it is located on a disordered segment that emerges from the C‐terminus of the β‐subunit (‘C’; magenta).
Figure 4. Clathrin:protein interactions and the line‐fishing model for clathrin recruitment. (a) Ribbon model of the seven‐bladed clathrin TD (cyan, with blades numbered 1–7 from the N‐ to C‐terminus) shown with clathrin binding peptides derived from interacting proteins: peptides from the beta‐3 subunit of AP‐3 [purple; pdb 1C9I (ter Haar et al., )], amphiphysin [yellow; pdb 1UTC (Miele et al., )], and β arrestin 1 splice loop [green; pdb 3GC3 (Kang et al., )] are shown as they occur in the crystal structures of the respective TD:peptide complexes. (b) A surface representation of the clathrin TD with residue peaks significantly broadened or shifted by a clathrin‐box peptide derived from the AP‐2 adaptor highlighted in red (site 1), blue (site 2) or green (site 3). Peptides from the beta‐3 subunit of AP‐3 (purple), amphiphysin (yellow), and the beta arrestin 1 splice loop (green) are shown as they occur in the crystal structures of the respective TD:peptide complexes. For each site, a representative residue peak that is shifted by the AP‐2 peptide is shown and coloured black, red, orange, green, blue and purple; corresponding, respectively, to TROSY‐HSQC spectra collected at peptide:TD ratios of 0:1, 1:1, 2:1, 3:1, 5:1 and 9:1. The background shows the 2‐D 1H‐15N TROSY‐HSQC spectrum of the TD molecule. Similar results were found with two clathrin‐box peptides from the clathrin binding domain of AP180 (Zhuo et al., ). (c) Structure of the AP180 assembly protein [pdb 1hfa (Ford et al., )]. Its structured ANTH domain binds membranes through an interaction with the phosphoinositide PI(4,5)P2 (Hao et al., ). Its unstructured C‐terminal domain binds clathrin through interactions with 12 clathrin box sequences (red) that are scattered throughout this domain (Morgan et al., ). (d) The line fishing model for clathrin recruitment. The long unstructured part of AP180 can scan a large volume of space and rapidly engage clathrin molecules through its multiple clathrin binding elements. However, the interactions with each of these elements is weak and dynamic, allowing the clathrin to move and reorient as it fits into the growing lattice on the membranes (Zhuo et al., ).


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Further Reading

Brodsky FM (2012) Diversity of clathrin function: new tricks for an old protein. Annual Review of Cell and Developmental Biology 28: 309–336.

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Lafer, Eileen M, and Sousa, Rui(Apr 2017) Clathrin. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027012]