Picking the clathrin lock

Abstract

Endocytic cargos are ensheathed in a clathrin coat—a complicated woven lattice that looks like it could never be pried apart. Yet uncoating occurs soon after vesicles are released from the plasma membrane, thanks to Hsc70 and its cochaperone auxilin. New structures of the clathrin coat with and without auxilin reveal a possible latch that might spring open to release the clathrin lock. Figure Clathrin comes apart when auxilin (left inset, red) targets the tripod (blue, right inset). The structures come from Alexander Fotin, Tomas Kirchhausen, Stephen Harrison, Thomas Walz (Harvard Medical School, Boston, MA), and colleagues. Existing electron micrograph (EM) structures were “unsatisfying,” says Kirchhausen, because “you couldn't see the contacts.” The Boston team selected the best of their EM images of purified clathrin cages, clustered the images by orientation, and removed error-prone, distorted structures. After fitting the computer-generated structure with existing X-ray structures of short segments of clathrin, the result was a resolution improvement from 21 to 7.9 A. Each clathrin trimer is a three-legged construction joined at a single hip, or vertex. The three legs sprawl out leaving knees at three adjacent vertices and ankles at three more distant vertices. Any given vertex therefore has a hip and, from other neighboring trimers, three knees and three ankles. The new structure reveals a tripod of short rods that reaches down from the hip to lock the triangular barrel of three neighbors' ankles in place. The auxilin is positioned right near this crucial contact, and distorts the ankles in a way that should help to undo the tripod's latch, perhaps exposing the ends of the tripod's barrels. In the cell Hsc70 might grab onto these newly exposed barrels and thus keep them from reattaching to the ankles. Confirmation of this model will require structures that include Hsc70, and visualization of the uncoating process itself. Uncoating is a rapid, catastrophic event, but Kirchhausen believes that new, fast, live-imaging setups may be able to capture it. Reference: Fotin, A., et al. 2004. Nature. doi:.10.1038/nature03079 [PubMed] [Cross Ref] Fotin, A., et al. 2004. Nature. doi:.10.1038/nature03078 [PubMed] [Cross Ref]