Article
- The EMBO Journal (2004) 23, 511 - 519
- doi:10.1038/sj.emboj.7600060
Published online: 22 January 2004
Subject Categories:
Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery
Philippe Meyer1,ab, Chrisostomos Prodromou1,b, Chunyan Liao2, Bin Hu2, S Mark Roe1, Cara K Vaughan1, Ignacija Vlasic2, Barry Panaretou2, Peter W Piper3,c and Laurence H Pearl1
- Chester Beatty Laboratories, Section of Structural Biology, The Institute of Cancer Research, London, UK
- Division of Life Sciences, King's College London, London, UK
- Department of Biochemistry and Molecular Biology, University College London, London, UK
Correspondence to:
Laurence H Pearl, Chester Beatty Laboratories, Section of Structural Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. Tel.: +44 0207 970 6045/6; Fax: +44 0207 970 6051; E-mail: laurence.pearl@icr.ac.uk
aPresent address: Laboratoire d'Enzymologie et de Biochimie Structurales, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
bThese authors made equal contributions
cPresent address: Department of Molecular Biology and Biotechnology, The University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK
Received 24 June 2003; Accepted 9 December 2003
Abstract
Hsp90 is a molecular chaperone essential for the activation and assembly of many key eukaryotic signalling and regulatory proteins. Hsp90 is assisted and regulated by co-chaperones that participate in an ordered series of dynamic multiprotein complexes, linked to Hsp90s conformationally coupled ATPase cycle. The co-chaperones Aha1 and Hch1 bind to Hsp90 and stimulate its ATPase activity. Biochemical analysis shows that this activity is dependent on the N-terminal domain of Aha1, which interacts with the central segment of Hsp90. The structural basis for this interaction is revealed by the crystal structure of the N-terminal domain (1–153) of Aha1 (equivalent to the whole of Hch1) in complex with the middle segment of Hsp90 (273–530). Structural analysis and mutagenesis show that binding of N-Aha1 promotes a conformational switch in the middle-segment catalytic loop (370–390) of Hsp90 that releases the catalytic Arg 380 and enables its interaction with ATP in the N-terminal nucleotide-binding domain of the chaperone.
Keywords:
- co-chaperone,
- molecular chaperone,
- regulation
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