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

Mohamed F AlAjmi¹, Shama Khan², Arunabh Choudhury³

¹Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Frontiers in Molecular Biosciences

|November 22, 2021

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.

Insights

Mutations in Serum and glucocorticoid-regulated kinase 1 (SGK1) can cause functional loss, impacting cell processes and disease. Molecular dynamics simulations revealed significant conformational changes, particularly with the T256A mutation, highlighting its role in disease progression.

Area of Science:

Biochemistry
Molecular Biology
Structural Biology

Background:

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a key Ser/Thr protein kinase.
SGK1 dysregulation is implicated in various cancers, including breast, prostate, and lung carcinomas.
Understanding SGK1 mutations is crucial for disease progression insights.

Purpose of the Study:

To computationally analyze SGK1 mutations at sequence and structural levels.
To investigate the impact of specific SGK1 mutations on protein stability and dynamics.
To elucidate the molecular mechanisms underlying SGK1 dysfunction in disease.

Main Methods:

Utilized state-of-the-art computational approaches for mutation analysis.
Performed all-atom molecular dynamic (MD) simulations for 200 ns.
Analyzed sequence and structural impacts of identified pathogenic mutations.

Main Results:

Identified several pathogenic and destabilizing SGK1 mutations.
Observed substantial conformational alterations in SGK1 structure due to mutations.
The T256A mutation showed a particularly significant impact, leading to functional loss.

Conclusions:

SGK1 mutations can lead to significant functional loss and conformational changes.
These alterations contribute to disease progression, including cancer and neurodegeneration.
Computational analysis provides valuable insights into SGK1-related pathologies.

Read full analysis

Keywords:

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

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