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.
Highlights
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
In order to study the pathogenic pattern of AR mutants in related diseases, our computational analysis consist of the following steps as in Fig. 1: (1) extracted AR variations from the following four databases: ARDB (The androgen receptor gene mutations database: 2012 update; https://androgendb.mcgill.ca), HGMD (Human Gene Mutation Database, 2015), Cosmic (2018.10.01), 1,000 genome; (2) analyzed mutation frequency, protein stability and Scientific Reports | (2020) 10:12101 |
AR N-terminal domain (NTD) contains polyglutamine and polyglycine repeats, and the length of these two repeats is highly variable in the human p opulation[43,44]
Summary
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. Protein stability is a fundamental property that affects protein configuration, activity and regulation It plays an essential role in evolution, a variety of diseases and industrial applications[1,2,3,4]. The most common cause of monogenic diseases is single-nucleotide variation (SNV) leading to amino acid substitutions These missense variants can have a strong effect on the stability of a protein, leading to detrimental changes to protein function. Androgens play key role in regulating behavior, spermatogenesis and bone m etabolism[9] Androgens mediate their actions primarily via the androgen receptor. AR plays an important role in the development and metastasis of several hormone-related cancers, including prostate cancer[12], breast cancer[16,17], liver cancer[18,19,20]
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