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Linking multipoint folding and stability with functional regulation in the mitochondrial transmembrane β-barrel Sam50
Roshika Ravi1, Swadha Gupta1, Jyoti Kumari1
1Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
Nature Communications
|April 2, 2026
Summary
Researchers identified key residues regulating the structure and function of the essential mitochondrial protein Sam50. Destabilizing hotspots correlate with its gating function, revealing insights into protein folding and assembly.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Mitochondrial outer membrane proteins (β-OMPs) mediate cellular interactions.
- Sam50, a crucial β-OMP, is vital for eukaryotic cell viability.
- The molecular regulation of Sam50 remains largely unknown.
Purpose of the Study:
- To identify and characterize residues governing Sam50 structure and function.
- To elucidate the folding mechanism and stability of Sam50.
- To investigate the relationship between Sam50 structure, folding, and its gating function.
Main Methods:
- Single-molecule electrophysiology
- In vivo functional assays
- Protein stability measurements (165 Xaa→Ala substitutions)
- Per-residue stability analysis
Main Results:
- The POlypeptide-TRansport Associated domain is dispensable for Sam50.
- Sam50 folds via parallel pathways with N-terminal folding nucleus and C-terminal frustration.
- Destabilizing hotspots in Sam50 are linked to its gating mechanism.
- Specific residues regulate folding, stability, and function, influencing mutation sensitivity.
Conclusions:
- Sam50's dynamic structure, regulated by specific residues, provides functional advantages.
- Understanding Sam50 folding and stability is crucial for its role in mitochondrial assembly and function.
- Residue-specific regulation impacts Sam50's gating and sensitivity to mutations.
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