Article
- The EMBO Journal (2007) 26, 600 - 612
- doi:10.1038/sj.emboj.7601501
Published online: 11 January 2007
Subject Categories:
Structural insight into the ESCRT-I/-II link and its role in MVB trafficking
David J Gill1, Hsiangling Teo1, Ji Sun2, Olga Perisic1, Dmitry B Veprintsev3, Scott D Emr2 and Roger L Williams1
- MRC Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, UK
- Department of Cellular and Molecular Medicine, The Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Centre for Protein Engineering, Medical Research Council Centre, Cambridge, UK
Correspondence to:
David J Gill, Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Hills Road, Cambridge, Cambridgeshire CB2 2QH, UK. Tel.: +44 1223 402164; Fax: +44 1223 412178; E-mail: djg38@mrc-lmb.cam.ac.uk
Received 22 August 2006; Accepted 20 November 2006
Abstract
ESCRT (endosomal sorting complex required for transport) complexes orchestrate efficient sorting of ubiquitinated transmembrane receptors to lysosomes via multivesicular bodies (MVBs). Yeast ESCRT-I and ESCRT-II interact directly in vitro; however, this association is not detected in yeast cytosol. To gain understanding of the molecular mechanisms of this link, we have characterised the ESCRT-I/-II supercomplex and determined the crystal structure of its interface. The link is formed by the vacuolar protein sorting (Vps)28 C-terminus (ESCRT-I) binding with nanomolar affinity to the Vps36-NZF-N zinc-finger domain (ESCRT-II). A hydrophobic patch on the Vps28-CT four-helix bundle contacts the hydrophobic knuckles of Vps36-NZF-N. Mutation of the ESCRT-I/-II link results in a cargo-sorting defect in yeast. Interestingly, the two Vps36 NZF domains, NZF-N and NZF-C, despite having the same core fold, use distinct surfaces to bind ESCRT-I or ubiquitinated cargo. We also show that a new component of ESCRT-I, Mvb12 (YGR206W), engages ESCRT-I directly with nanomolar affinity to form a 1:1:1:1 heterotetramer. Mvb12 does not affect the affinity of ESCRT-I for ESCRT-II in vitro. Our data suggest a complex regulatory mechanism for the ESCRT-I/-II link in yeast.
Keywords:
- CHMP,
- ESCRT,
- HIV budding,
- MVB,
- NZF finger
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