Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation.

Mohamed F Alajmi,Vrushali Chimankar,Taj Mohammad,Mathew Suji Eapen,Shama Khan,Arunabh Choudhury,Saba Noor,Wenying Lu,Abdelbaset Mohamed Elasbali,Sukhwinder Singh Sohal,Afzal Hussain,Md Imtaiyaz Hassan,Philip M Hansbro

doi:10.3389/fmolb.2021.780284

Abstract

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration.

Highlights

Cancer progression is the result of malfunction at multiple cellular levels, including abnormal gene expression, metabolic conditions, abnormal signal transduction, epithelial to mesenchymal transition, genetic, and epigenetic alterations (Sekido, 2010; Mahmood et al, 2017; Lu et al, 2020)
We examined a range of mutations and characterized their deleterious impact on the structure and function of Serum and glucocorticoid-regulated kinase 1 (SGK1), which may contribute to disease development and progression, such as cancer and neurodegeneration
Single amino acid substitutions are among the most frequent genetic variations associated with numerous diseases, including cancer and neurodegeneration

Summary

Introduction

Cancer progression is the result of malfunction at multiple cellular levels, including abnormal gene expression, metabolic conditions, abnormal signal transduction, epithelial to mesenchymal transition, genetic, and epigenetic alterations (Sekido, 2010; Mahmood et al, 2017; Lu et al, 2020). Deleterious Mutations in SGK1 of the AGC family of Serine/Threonine protein kinases that regulate the survivability and growth of cells (Lang et al, 2010). It is involved in regulating cell cycle progression, proliferation, differentiation and apoptosis, and is associated with the onset and progression of various cancers in humans (Sang et al, 2021). SGK1 is acutely regulated at various levels, including gene transcription and post-translationally by phosphorylation and ubiquitination It is expressed in several tissues, including the spleen, thymus, bone marrow, breast, prostate, and oral epithelial (Eapen et al, 2019)

Methods

Results

Discussion

Conclusion