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Glycine at Position 93 in SOD1: Mutation-Sensitivity Landscape and Context-Dependent Folding Requirements
Min-Kyung Nam1, Battur Tserennadmid2, Gi Heon Jeong1
1Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Biochemistry
|February 2, 2026
Summary
Altering glycine at position 93 in SOD1 causes protein misfolding and aggregation. The properties of substituted amino acids dictate the specific destabilization pathways, impacting protein structure and stability.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Glycine, the simplest amino acid, is vital for protein folding and flexibility.
- Copper/zinc superoxide dismutase (SOD1) is a key enzyme in cellular defense against oxidative stress.
Purpose of the Study:
- To investigate the impact of glycine substitution at position 93 (G93) in SOD1 on protein structure and stability.
- To understand how physicochemical properties of amino acid substitutions influence protein misfolding and aggregation.
Main Methods:
- Engineering of 19 G93 SOD1 mutants.
- Evaluation of folding patterns and aggregation using immunoblotting.
- Fluorescence microscopy and fluorescence loss in photobleaching (FLIP) assays.
Main Results:
- All G93 SOD1 mutants formed aggregates with varied stability, indicating extreme mutation sensitivity at this position.
- Distinct destabilization pathways were observed depending on the physicochemical properties (polarity, charge, steric bulk) of the substituting amino acid.
- Nonpolar substitutions favored hydrophobic interactions, while polar/charged substitutions utilized hydrogen bonding and electrostatic interactions for aggregation.
Conclusions:
- Glycine's minimal side chain is critical for maintaining native protein structure.
- Side chain properties significantly modulate protein folding, stability, and aggregation propensity.
- Findings offer mechanistic insights into protein aggregation relevant to neurodegenerative diseases.
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