Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions.
Activation of client proteins by the Hsp90 molecular chaperone is dependent on binding and hydrolysis of ATP, which drives a molecular clamp via transient dimerization of the N-terminal domains. The crystal structure of the middle segment of yeast Hsp90 reveals considerable evolutionary divergence from the equivalent regions of other GHKL protein family members such as MutL and GyrB, including an additional domain of new fold. Using the known structure of the N-terminal nucleotide binding domain, a model for the Hsp90 dimer has been constructed. From this structure, residues implicated in the ATPase-coupled conformational cycle and in interactions with client proteins and the activating cochaperone Aha1 have been identified, and their roles functionally characterized in vitro and in vivo.
Meyer
Philippe
P
Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, London, United Kingdom.
Prodromou
Chrisostomos
C
Hu
Bin
B
Vaughan
Cara
C
Roe
S Mark
SM
Panaretou
Barry
B
Piper
Peter W
PW
Pearl
Laurence H
LH
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D002455:Cell Division; D018360:Crystallography, X-Ray; D027081:DNA Gyrase / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000070956:MutL Proteins; D009154:Mutation; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013696:Temperature
D029968:Escherichia coli Proteins; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; C074770:MutL protein, E coli; D000255:Adenosine Triphosphate; D015688:Oncogene Protein pp60(v-src); D000251:Adenosine Triphosphatases; D000070956:MutL Proteins; D027081:DNA Gyrase