Structure network-based landscape of rhodopsin misfolding by mutations and algorithmic prediction of small chaperone action

Failure of a protein to achieve its functional structural state and normal cellular location contributes to the etiology and pathology of heritable human conformational diseases. The autosomal dominant form of retinitis pigmentosa (adRP) is an incurable blindness largely linked to mutations of the membrane protein rod opsin. While the mechanisms underlying the noxious effects of the mutated protein are not completely understood, a common feature is the functional protein conformational loss. Here, the wild type and 39 adRP rod opsin mutants were subjected to mechanical unfolding simulations coupled to the graph theory-based protein structure network analysis. A robust computational model was inferred and in vitro validated in its ability to predict endoplasmic reticulum retention of adRP mutants, a feature linked to the mutation-caused misfolding. The structurebased approach could also infer the structural determinants of small chaperone action on misfolded protein mutants with therapeutic implications. The approach is exportable to conformational diseases linked to missense mutations in any membrane protein. (C) 2021 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

Automated summary

This study employed a computational model to predict the endoplasmic reticulum retention of RP mutants and determine the structural determinants of small chaperone action on misfolded protein mutants with therapeutic implications. The approach is applicable to conformational diseases linked to missense mutations in any membrane protein.