Exploring the Functional Complementation between Grp94 and Hsp90.
Kevin A. Maharaj,Kevin A. Maharaj,Nanette L.S. Que,Feng Hong,John D. Huck,John D. Huck,Sabrina K. Gill,Shuang Wu,Zihai Li,Daniel T. Gewirth,Daniel T. Gewirth +10 more
TL;DR: It is shown that the N-terminal domain or the combination of the second lobe of the Middle domain plus the C-terminale domain of Grp94 can functionally substitute for their yeast Hsp90 counterparts but that the equivalent HSp90 domains cannot functionally replace their counterparts in Grp 94.
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Abstract: 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.
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Citations
Structural and Functional Analysis of GRP94 in the Closed State Reveals an Essential Role for the Pre-N Domain and a Potential Client-Binding Site.
TL;DR: It is shown that the GRP94 pre-N domain is essential for client maturation, and it is identified as an important regulator of ATPase rates and dimer closure and the results provide structural insight into the ATP-dependent client maturation process of GRP 94.
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Different Grp94 components interact transiently with the myocilin olfactomedin domain in vitro to enhance or retard its amyloid aggregation.
TL;DR: It is shown that the Grp94 N-terminal nucleotide-binding N domain is responsible for accelerating OLF aggregation in vitro, and further supports drug discovery efforts to inhibit these interactions as a strategy to treat myocilin-associated glaucoma.
The GRP94 gene of Yesso scallop (Patinopecten yessoensis): Characterization and expression regulation in response to thermal and bacterial stresses.
Shuyue Wang,Xu Li,Tingting Li,Huizhen Wang,Xiangchao Zhang,Jiarun Lou,Qiang Xing,Xiaoli Hu,Zhenmin Bao +8 more
TL;DR: The results suggest the involvement of PyGRP94 in response to thermal stress, and that it might play an important role in the innate immune defense of scallop.
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Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects.
Shicheng Xu,An-ping Guo,Nan-Nan Chen,Wei Dai,Huan-aoyu Yang,Wenqin Xie,Mengjie Wang,Qidong You,Xiao-Li Xu +8 more
TL;DR: In this article, a new series of Grp94 inhibitors based on Phe199 induced fit mechanism was developed, using an alkynyl-containing inhibitor as a starting point, which showed potent inhibitory activity toward Grp 94 in a fluorescence polarization-based assay.
7
Pre-N and C-terminal extension regions of Arabidopsis HSP90.7 regulate the chaperone activity and ER stress response
Jenan Noureddine,Adheip Monikantan Nair,Kenneth Andrei Espinosa,Linlin Fan,Joyce Cheng,Rongmin Zhao,Jenan Noureddine,Adheip Monikantan Nair,Kenneth Andrei Espinosa,Linlin Fan,Joyce Cheng,Rongmin Zhao +11 more
TL;DR: This study elucidates the regulatory roles of pre-N-terminal and C-terminal extension regions of Arabidopsis HSP90.7 in chaperone activity and ER stress response, revealing conserved regulatory functions and specialized roles in ER homeostasis and plant stress resilience.
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