Left‐handed conformations of glycyl residues may confer protection against protein aggregation
Year: 2025
Type: article
Abstract: The lack of Cβ atom allows glycyl to adopt left‐handed Ramachandran conformations, typically disallowed for l ‐amino acids. The underlying significance remains under‐appreciated. Through conformational analysis of glycyls at 1104 disease and 343 benign variant sites, we show that the left‐handed glycyls are over‐represented (odds ratio > 1.3) at disease variant sites and are evolutionarily conserved. Mutations involving l ‐disallowed glycyls destabilize native folding by altering free energies ( P = 2.4 × 10 –4 ). The l ‐disallowed glycyls are enriched at the aggregation gatekeepers, more profoundly so in thermophiles ( P = 2.0 × 10 –6 ), implying heightened selection to impede aggregation. Mutations of l ‐disallowed glycyls also reduce the protein solubility ( P = 0.001). Due to mostly positive Φ dihedral‐angle, Cα atom of l ‐disallowed glycyl flips to conform a crescent that likely disrupts β‐strand alignment, discouraging the intermolecular aggregation of β‐strands. Deep learning confirms the predictive value of l ‐disallowed glycyls in identifying pathogenic variants (accuracy = 0.81 vs. 0.69, area under the curve = 0.88 vs. 0.79). The findings underscore the evolutionary selection of l ‐disallowed conformations of glycyls to maintain proteostasis by modulating protein stability and aggregation, and suggest applications for disease‐associated genetic prioritization and soluble protein design.
Source: FEBS Journal
DOI: 10.1111/febs.70092
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G3435564602, G3861023292
OpenAlex ID: W4409544128