Chaperoned ubiquitylation - Crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex

Minghao Zhang, Mark Windheim, S. Mark Roe, Mark Peggie, Philip Cohen, Chrisostomos Prodromou, Laurence H. Pearl

    Research output: Contribution to journalArticle

    293 Citations (Scopus)

    Abstract

    CHIP is a dimeric U box E3 ubiquitin ligase that binds Hsp90 and/or Hsp70 via its TPR-domain, facilitating ubiquitylation of chaperone bound client proteins. We have determined the crystal structure of CHIP bound to an Hsp90 C-terminal decapeptide. The structure explains how CHIP associates with either chaperone type and reveals an unusual asymmetric homodimer in which the protomers adopt radically different conformations. Additionally, we identified CHIP as a functional partner of Ubc13-Uev1a in formation of Lys63-linked polyubiquitin chains, extending CHIP's roles into ubiquitin regulation as well as targeted destruction. The structure of Ubc13-Uev1a bound to the CHIP U box domain defines the basis for selective cooperation of CHIP with specific ubiquitin-conjugating enzymes. Remarkably, the asymmetric arrangement of the TPR domains in the CHIP dimer occludes one Ubc binding site, so that CHIP operates with half-of-sites activity, providing an elegant means for coupling a dimeric chaperone to a single ubiquitylation system.

    Original languageEnglish
    Pages (from-to)525-538
    Number of pages14
    JournalMolecular Cell
    Volume20
    Issue number4
    DOIs
    Publication statusPublished - 23 Nov 2005

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