title: Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery.
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 Hsp90 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.
authors.affiliation: Chester Beatty Laboratories, Section of Structural Biology, The Institute of Cancer Research, London, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Meyer
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liao
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Cara K
authors.initials: CK
authors.lastname: Vaughan
authors.forename: Ignacija
authors.initials: I
authors.lastname: Vlasic
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
authors.forename: Peter W
authors.initials: PW
authors.lastname: Piper
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D018833:Chaperonins; D016153:Genes, Suppressor; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C475092:AHA1 protein, S cerevisiae; C117748:HCH1 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases; D018833:Chaperonins