Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity

Area of Science:

• Mitochondrial biology
• Structural biology
• Molecular dynamics

Background:

• The mitochondrial chaperone TRAP1 regulates cellular homeostasis, with implications in neurodegeneration, ischemia, and cancer.
• TRAP1 mutations are linked to disorders, but the structural basis for their functional impact remains unstudied.

Purpose of the Study:

• To investigate the structural and functional consequences of five specific TRAP1 mutations.
• To elucidate the structure-activity relationship of TRAP1 and identify key regulatory residues.

Main Methods:

• Utilized a modular structure-based framework.
• Performed molecular dynamics simulations to analyze mutation effects.
• Assessed impacts on TRAP1 stability, dynamics, and ATPase activity.
• Evaluated effects on TRAP1 interactor succinate dehydrogenase (SDH) activity.

Main Results:

• Each mutation differentially affected TRAP1's long-range interactions, dynamics, and ATPase activity.
• Mutations altered SDH activity, indicating functional changes in TRAP1.
• TRAP1 mutations impacted aggressive sarcoma cell growth, migration, and drug sensitivity.

Conclusions:

• Provides novel insights into the structure-activity relationship of TRAP1.
• Identifies critical amino acid residues governing TRAP1 proteostatic and pro-neoplastic functions.
• Highlights the potential of targeting TRAP1 in cancer therapy.