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Structure network-based landscape of rhodopsin misfolding by mutations and algorithmic prediction of small chaperone action
Computational and Structural Biotechnology Journal ( IF 6 ) Pub Date : 2021-11-02 , DOI: 10.1016/j.csbj.2021.10.040
Angelo Felline 1 , Davide Schiroli 2 , Antonella Comitato 2 , Valeria Marigo 2, 3 , Francesca Fanelli 1, 3
Affiliation  

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 structure-based 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.



中文翻译:

基于结构网络的视紫红质错误折叠景观和小分子伴侣作用的算法预测

蛋白质未能实现其功能性结构状态和正常细胞定位会导致可遗传的人类构象疾病的病因学和病理学。色素性视网膜炎 (adRP) 的常染色体显性遗传形式是一种无法治愈的失明,主要与膜蛋白棒视蛋白的突变有关。虽然突变蛋白质有害作用的潜在机制尚不完全清楚,但一个共同的特征是功能性蛋白质构象丢失。在这里,野生型和 39 个 adRP 杆状视蛋白突变体接受了机械展开模拟,并结合基于图论的蛋白质结构网络分析。

一个强大的计算模型被推断并在体外验证了其预测 adRP 突变体的内质网保留的能力,这一特征与突变引起的错误折叠有关。基于结构的方法还可以推断小分子伴侣作用对错误折叠的蛋白质突变体的结构决定因素,具有治疗意义。

该方法可用于与任何膜蛋白中的错义突变相关的构象疾病。

更新日期:2021-11-02
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