Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery

Meyer, Philippe, Prodromou, Chrisostomos, Liao, Chunyan, Hu, Bin, Roe, S Mark, Vaughan, Cara K, Vlasic, Ignacija, Panaretou, Barry, Piper, Peter W and Pearl, Laurence H (2004) Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. EMBO Journal, 23 (6). pp. 1402-1410. ISSN 0261-4189

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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.

Item Type: Article
Keywords: Adenosine Triphosphatases/*chemistry/genetics/*metabolism Amino Acid Sequence Binding Sites Catalysis Chaperonins Genes, Suppressor HSP90 Heat-Shock Proteins/*chemistry/genetics/*metabolism Models, Molecular Molecular Chaperones Molecular Sequence Data Protein Binding Protein Structure, Secondary Protein Structure, Tertiary Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism Sequence Alignment Structure-Activity Relationship
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Q Science > QD Chemistry > QD0901 Crystallography
Depositing User: Chrisostomos Prodromou
Date Deposited: 25 Feb 2015 07:05
Last Modified: 25 Feb 2015 09:27
URI: http://sro.sussex.ac.uk/id/eprint/44341
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