Exploring the Functional Complementation between Grp94 and Hsp90.
Grp94 and Hsp90 are the ER and cytoplasmic paralog members, respectively, of the hsp90 family of molecular chaperones. The structural and biochemical differences between Hsp90 and Grp94 that allow each paralog to efficiently chaperone its particular set of clients are poorly understood. The two paralogs exhibit a high degree of sequence similarity, yet also display significant differences in their quaternary conformations and ATPase activity. In order to identify the structural elements that distinguish Grp94 from Hsp90, we characterized the similarities and differences between the two proteins by testing the ability of Hsp90/Grp94 chimeras to functionally substitute for the wild-type chaperones in vivo. We show that the N-terminal domain or the combination of the second lobe of the Middle domain plus the C-terminal domain of Grp94 can functionally substitute for their yeast Hsp90 counterparts but that the equivalent Hsp90 domains cannot functionally replace their counterparts in Grp94. These results also identify the interface between the Middle and C-terminal domains as an important structural unit within the Hsp90 family.
Hauptman-Woodward Medical Research Institute, Buffalo, New York, United States of America.|Department of Structural Biology, University at Buffalo, Buffalo, New York, United States of America.
Kevin A
KA
Maharaj
Hauptman-Woodward Medical Research Institute, Buffalo, New York, United States of America.
Nanette L S
NL
Que
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Feng
F
Hong
Hauptman-Woodward Medical Research Institute, Buffalo, New York, United States of America.|Department of Structural Biology, University at Buffalo, Buffalo, New York, United States of America.
John D
JD
Huck
Hauptman-Woodward Medical Research Institute, Buffalo, New York, United States of America.
Sabrina K
SK
Gill
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Shuang
S
Wu
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Zihai
Z
Li
Hauptman-Woodward Medical Research Institute, Buffalo, New York, United States of America.|Department of Structural Biology, University at Buffalo, Buffalo, New York, United States of America.
Daniel T
DT
Gewirth
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D004285:Dogs; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism; D000072417:Protein Domains; D012441:Saccharomyces cerevisiae / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C018551:glucose-regulated proteins; D000251:Adenosine Triphosphatases