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Symmetry broken and rebroken during the ATP hydrolysis cycle of the mitochondrial Hsp90 TRAP1
- Source :
- eLife, Vol 6 (2017), eLife
- Publication Year :
- 2017
- Publisher :
- eLife Sciences Publications, Ltd, 2017.
-
Abstract
- Hsp90 is a homodimeric ATP-dependent molecular chaperone that remodels its substrate “client” proteins, facilitating their folding and activating them for biological function. Despite decades of research, the mechanism connecting ATP hydrolysis and chaperone function remains elusive. Particularly puzzling has been the apparent lack of cooperativity in hydrolysis of the ATP in each protomer. A crystal structure of the mitochondrial Hsp90, TRAP1, revealed that the catalytically active state is closed in a highly-strained asymmetric conformation. This asymmetry, unobserved in other Hsp90 homologs, is due to buckling of one of the protomers and is most pronounced at the broadly conserved client-binding region. Here, we show that rather than being cooperative or independent, ATP hydrolysis on the two protomers is sequential and deterministic. Moreover, dimer asymmetry sets up differential hydrolysis rates for each protomer, such that the buckled conformation favors ATP hydrolysis. Remarkably, after the first hydrolysis, the dimer undergoes a flip in the asymmetry while remaining in a closed state for the second hydrolysis. From these results, we propose a model where direct coupling of ATP hydrolysis and conformational flipping rearranges client-binding sites, providing a paradigm of how energy from ATP hydrolysis can be used for client remodeling.
- Subjects :
- Models, Molecular
0301 basic medicine
Protein Conformation
Dimer
Cooperativity
Protomer
Crystallography, X-Ray
Biochemistry
chemistry.chemical_compound
Adenosine Triphosphate
ATP hydrolysis
Catalytic Domain
chaperone
Biology (General)
Zebrafish
0303 health sciences
biology
Chemistry
Hydrolysis
General Neuroscience
030302 biochemistry & molecular biology
General Medicine
Biophysics and Structural Biology
Hsp90
Medicine
asymmetry
Research Article
QH301-705.5
homodimer
Science
General Biochemistry, Genetics and Molecular Biology
TRAP1
03 medical and health sciences
None
Animals
Humans
HSP90 Heat-Shock Proteins
030304 developmental biology
General Immunology and Microbiology
Zebrafish Proteins
TNF Receptor-Associated Factor 1
030104 developmental biology
Structural biology
Chaperone (protein)
biology.protein
Biophysics
Protein Multimerization
Function (biology)
Subjects
Details
- ISSN :
- 2050084X
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....12a70fc691b776f69319959fbfba2025