Conformational plasticity of a BiP-GRP94 chaperone complex.
Joel Cyrille Brenner1, Linda Charlotte Zirden2, Lana Buzuk1
1Department of Mechanistic Cell Biology, Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
Nature Structural & Molecular Biology
|July 14, 2025
Summary
Heat shock proteins (Hsp70) and heat shock protein 90 (Hsp90) directly cooperate to maintain protein homeostasis. This study reveals the structural basis for BiP-GRP94 chaperone complex formation and function.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Heat shock proteins (Hsp70 and Hsp90) are crucial for protein homeostasis.
- Glucose-regulated protein 94 (GRP94) is the sole Hsp90 in the secretory pathway, vital for protein maturation.
- The mechanism of BiP (Hsp70) regulating GRP94 conformation, independent of cochaperones, was unknown.
Purpose of the Study:
- To biochemically and structurally characterize the BiP-GRP94 chaperone complex.
- To elucidate the structural basis of BiP-mediated GRP94 conformational changes.
- To understand the direct cooperation between Hsp70 and Hsp90.
Main Methods:
- Biochemical assays to study chaperone complex formation.
- Structural biology techniques to visualize complex structures.
- Analysis of protein-protein interactions.
Main Results:
- BiP binds to an open GRP94 dimer via a conserved interface.
- A second BiP stabilizes a semiclosed GRP94 dimer, facilitating substrate loading.
- A novel mechanism of direct Hsp70-Hsp90 cooperation, independent of cochaperones, was identified.
Conclusions:
- The study reveals the structural mechanism for BiP-GRP94 complex formation and conformational transition.
- This work uncovers a fundamental pathway for direct Hsp70-Hsp90 cooperation in protein homeostasis.
- Findings provide insights into chaperone function in the secretory pathway.
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