Computational analysis of androgen receptor (AR) variants to decipher the relationship between protein stability and related-diseases.

Scientific Reports
Fangfang ChenJing Yu

Abstract

Although more than 1,000 androgen receptor (AR) mutations have been identified and these mutants are pathologically important, few theoretical studies have investigated the role of AR protein folding stability in disease and its relationship with the phenotype of the patients. Here, we extracted AR variant data from four databases: ARDB, HGMD, Cosmic, and 1,000 genome. 905 androgen insensitivity syndrome (AIS)-associated loss-of-function mutants and 168 prostate cancer-associated gain-of-function mutants in AR were found. We analyzed the effect of single-residue variation on the folding stability of AR by FoldX and guanidine hydrochloride denaturation experiment, and found that genetic disease-associated mutations tend to have a significantly greater effect on protein stability than gene polymorphisms. Moreover, AR mutants in complete androgen insensitivity syndrome (CAIS) tend to have a greater effect on protein stability than in partial androgen insensitive syndrome (PAIS). This study, by linking disease phenotypes to changes in AR stability, demonstrates the importance of protein stability in the pathogenesis of hereditary disease.

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Datasets Mentioned

BETA
CCDS14387.1

Methods Mentioned

BETA
protein folding
ubiquitination
gel filtration
Circular dichroism

Software Mentioned

FoldX
STRUM
Cosmic
Mutant2
CUPSAT
Eris

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