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Title | Cryo-EM structure and molecular dynamic simulations explain the enhanced stability and ATP activity of the pathological chaperonin mutant. |
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Journal, issue, pages | Structure, Vol. 32, Issue 5, Page 575-584.e3, Year 2024 |
Publish date | May 2, 2024 |
Authors | Aiza Syed / Jihang Zhai / Baolin Guo / Yuan Zhao / Joseph Che-Yen Wang / Lingling Chen / |
PubMed Abstract | Chaperonins Hsp60s are required for cellular vitality by assisting protein folding in an ATP-dependent mechanism. Although conserved, the human mitochondrial mHsp60 exhibits molecular characteristics ...Chaperonins Hsp60s are required for cellular vitality by assisting protein folding in an ATP-dependent mechanism. Although conserved, the human mitochondrial mHsp60 exhibits molecular characteristics distinct from the E. coli GroEL, with different conformational assembly and higher subunit association dynamics, suggesting a different mechanism. We previously found that the pathological mutant mHsp60 exhibits enhanced subunit association stability and ATPase activity. To provide structural explanations for the V72I mutational effects, here we determined a cryo-EM structure of mHsp60. Our structural analysis combined with molecular dynamic simulations showed mHsp60 with increased inter-subunit interface, binding free energy, and dissociation force, all contributing to its enhanced subunit association stability. The gate to the nucleotide-binding (NB) site in mHsp60 mimicked the open conformation in the nucleotide-bound state with an additional open channel leading to the NB site, both promoting the mutant's ATPase activity. Our studies highlight the importance of mHsp60's characteristics in its biological function. |
External links | Structure / PubMed:38412855 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.4 Å |
Structure data | EMDB-41854: Structure of Human Mitochondrial Chaperonin V72I Mutant |
Source |
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Keywords | CHAPERONE / chaperonin / human mitochondrial mHsp60 / hereditary spastic paraplegia SPG13 / cryo-EM / molecular dynamic simulation |