Structure of an auxilin-bound clathrin coat and its implications for the mechanism of uncoating

Alexander Fotin, Yifan Cheng, Nikolaus Grigorieff, Thomas Walz, Stephen C. Harrison and Tomas Kirchhausen ()
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Alexander Fotin: Harvard Medical School
Yifan Cheng: Harvard Medical School
Nikolaus Grigorieff: Brandeis University
Thomas Walz: Harvard Medical School
Stephen C. Harrison: Harvard Medical School, and Howard Hughes Medical Institute
Tomas Kirchhausen: Harvard Medical School

Nature, 2004, vol. 432, issue 7017, 649-653

Abstract: Abstract Clathrin-coated pits invaginate from specific membrane compartments and pinch off as coated vesicles. These vesicles then uncoat rapidly once released. The Hsc70 molecular chaperone effects the uncoating reaction, and is guided to appropriate locations on clathrin lattices by the J-domain-containing co-chaperone molecule auxilin1,2,3,4. This raises the question of how a local event such as ATP hydrolysis by Hsc70 can catalyse a global disassembly. Here, we have used electron cryomicroscopy to determine 12-Å-resolution structures of in-vitro-assembled clathrin coats in association with a carboxy-terminal fragment of auxilin that contains both the clathrin-binding region and the J domain. We have located the auxilin fragment by computing differences between these structures and those lacking auxilin (described in an accompanying paper5). Auxilin binds within the clathrin lattice near contacts between an inward-projecting C-terminal helical tripod and the crossing of two ‘ankle’ segments; it also contacts the terminal domain of yet another clathrin ‘leg’. It therefore recruits Hsc70 to the neighbourhood of a set of critical interactions. Auxilin binding produces a local change in heavy-chain contacts, creating a detectable global distortion of the clathrin coat. We propose a mechanism by which local destabilization of the lattice promotes general uncoating.

Date: 2004
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DOI: 10.1038/nature03078

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