Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation.

Alexey Rayevsky,Liudmyla Livshits,Inga Prokopenko,Dmytro Sirokha,Dmytro Lozhko,Dariia Samofalova,Olexandra Gorodna

doi:10.3390/life11070659

Abstract

Over 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I836S (ClinVarID: 974911) in a patient with complete AIS (CAIS) phenotype. In the present study, we applied a set of computational approaches for the structural analysis of the ligand-binding domains in a wild-type and mutant AR to evaluate the functional impact of the novel I836S mutation. We revealed that the novel I836S substitution leads to a shorter existence time of the ligand’s gating tunnel and internal cavity, occurring only in the presence of S836 phosphorylation. Additionally, the analysis of phosphorylation of the 836 mutant residues explained the negative impact on AR homodimerization, since monomer surface changes indirectly impacted the binding site. Our analyses provide evidence that I836S causes disruptions of AR protein functionality and development of CAIS clinical features in patients.

Highlights

Androgen insensitivity syndrome (AIS) is a genetic disorder of sex development (DSD) that occurs at a frequency of 1 in 20,000 live births, and is the most commonDSD in people with karyotype 46,XY [1]
All information about androgen receptor (AR) protein mutations that lead to AIS and their crystal structures were retrieved with the UniProt code P10275
Since I836S mutation is not directly related to protein–protein interaction (PPI) interface, we investigated the effect of ligand binding on a wild-type protein and determined the type of aforementioned structural changes that could be affected by the replacement of I836 residue

Summary

Introduction

Androgen insensitivity syndrome (AIS) is a genetic disorder of sex development (DSD) that occurs at a frequency of 1 in 20,000 live births, and is the most commonDSD in people with karyotype 46,XY [1]. The AR gene encodes for AR, which is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. This nuclear receptor superfamily includes estrogen, progesterone, mineralocorticoid, and glucocorticoid receptors. AR makes specific protein–protein interactions with several basal transcription factors, such as TBP (TATA box-binding protein) and TFIIF (transcription factor IIF). These interactions occur predominantly in the activation function-1 (AF1) region, located within a highly disordered N-terminal domain of AR [3]. A ligand-dependent interaction between the two AR termini is necessary for maximum activation of the full-length receptor [4,5,6,7]

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Conclusion