Crystal structure of an Hsp90–nucleotide–p23/Sba1 closed chaperone complex

By Maruf M. U. Ali, S. Roe, C. Vaughan, P. Meyer, B. Panaretou, Peter W. Piper, C. Prodromou, Laurence H. Pearl. Nature, 2006

966 citations recorded by the source corpus.

Hsp90 (heat shock protein of 90 kDa) is a ubiquitous molecular chaperone responsible for the assembly and regulation of many eukaryotic signalling systems and is an emerging target for rational chemotherapy of many cancers. Although the structures of isolated domains of Hsp90 have been determined, the arrangement and ATP-dependent dynamics of these in the full Hsp90 dimer have been elusive and contentious. Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1. The structure reveals the complex architecture of the ‘closed’ state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1. Contrary to expectations, the closed Hsp90 would not enclose its client proteins but provides a bipartite binding surface whose formation and disruption are coupled to the chaperone ATPase cycle.

Subfields: Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7d3e1484e3786c58de7fd8a8d000c07430bd227c

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In Molecular Biology

Citations in the corpus

Experimental illumination of a fitness landscape (2011, background): “Based on the sequence and structure (10) of Hsp90, we focused on a nineamino acid region that contains a diversity of different amino acids with positions that vary in both their level of phylogenetic conservation among diversely related eukaryotes and their physical environment (solvent exposed and”
Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function. (2016, background): “The ‘‘lid’’ region of the ATPase domain adopts distinct nucleotide-bound conformations (Ali et al., 2006; Prodromou et al., 1997) including transient dimerization when ATP and the co-chaperone p23 are bound that, in turn, mediate dramatic conformational changes of the full-length Hsp90 dimer…”
SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. (2014, background): “293T cells were co-transfected with a FLAGSMYD2 expression vector and four different lengths of HA-HSP90AB1 vectors ([1–724], [1–500], [250–724] and [500–724]).”