title: Client-loading conformation of the Hsp90 molecular chaperone revealed in the cryo-EM structure of the human Hsp90:Hop complex.
abstract: Hsp90 is an essential molecular chaperone required for the folding and activation of many hundreds of cellular "client" proteins. The ATP-dependent chaperone cycle involves significant conformational rearrangements of the Hsp90 dimer and interaction with a network of cochaperone proteins. Little is known about the mechanism of client protein binding or how cochaperone interactions modulate Hsp90 conformational states. We have determined the cryo-EM structure of the human Hsp90:Hop complex that receives client proteins from the Hsp70 chaperone. Hop stabilizes an alternate Hsp90 open state, where hydrophobic client-binding surfaces have converged and the N-terminal domains have rotated and match the closed, ATP conformation. Hsp90 is thus simultaneously poised for client loading by Hsp70 and subsequent N-terminal dimerization and ATP hydrolysis. Upon binding of a single Hsp70, the Hsp90:Hop conformation remains essentially unchanged. These results identify distinct functions for the Hop cochaperone, revealing an asymmetric mechanism for Hsp90 regulation and client loading.
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Southworth
authors.forename: David A
authors.initials: DA
authors.lastname: Agard
mesh_terms: D000255:Adenosine Triphosphate; D020285:Cryoelectron Microscopy; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000648:ultrastructure; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D011487:Protein Conformation; D055503:Protein Multimerization; D013499:Surface Properties; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D004220:Disulfides; C476884:HOPX protein, human; D018841:HSP90 Heat-Shock Proteins; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate