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

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

doi:10.3389/fmolb.2021.780284

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

Front Mol Biosci. 2021 Nov 3:8:780284. doi: 10.3389/fmolb.2021.780284. eCollection 2021.

Authors

Affiliations

¹ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
² Drug Discovery and Development Centre (H3D), University of Cape Town, Cape Town, South Africa.
³ Department of Computer Science, Jamia Millia Islamia, New Delhi, India.
⁴ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
⁵ Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia.
⁶ Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, NSW, Australia.
⁷ Priority Research Centre for Healthy Lungs and Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.
⁸ Clinical Laboratory Science, College of Applied Medical Sciences-Qurayyat, Jouf University, Sakakah, Saudi Arabia.

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.

Keywords: deleterious mutations; essential dynamics; molecular dynamics simulation; serum/glucocorticoid regulated kinase 1; single amino acid substitutions.