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Structural Consequences of IRS-2 nsSNPs and Implication for Insulin Receptor Substrate-2 Protein Stability

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Abstract

Single-Nucleotide Polymorphisms (SNPs) are common genetic variations implicated in human diseases. The non-synonymous SNPs (nsSNPs) affect the proteins’ structures and their molecular interactions with other interacting proteins during the accomplishment of biochemical processes. This ultimately causes proteins functional perturbation and disease phenotypes. The Insulin receptor substrate-2 (IRS-2) protein promotes glucose absorption and participates in the biological regulation of glucose metabolism and energy production. Several IRS-2 SNPs are reported in association with type 2 diabetes and obesity in human populations. However, there are no comprehensive reports about the protein structural consequences of these nsSNPs. Keeping in view the pathophysiological consequences of the IRS-2 nsSNPs, we designed the current study to understand their possible structural impact on coding protein. The prioritized list of the deleterious IRS-2 nsSNPs was acquired from multiple bioinformatics resources, including VEP (SIFT, PolyPhen, and Condel), PROVEAN, SNPs&GO, PMut, and SNAP2. The protein structure stability assessment of these nsSNPs was performed by MuPro and I-Mutant-3.0 servers via structural modeling approaches. The atomic-level structural and molecular dynamics (MD) impact of these nsSNPs were examined using GROMACS 2019.2 software package. The analyses initially predicted 8 high-risk nsSNPs located in the highly conserved regions of IRS-2. The MD simulation analysis eventually prioritized the N232Y, R218C, and R104H nsSNPs that predicted to significantly compromise the structure stability and may affect the biological function of IRS-2. These nsSNPs are predicted as high-risk candidates for diabetes and obesity. The validation of protein structural impact of these shortlisted nsSNPs may provide biochemical insight into the IRS-2-mediated type-2 diabetes.

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Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

The authors acknowledge the financial support of Higher Education Commission (HEC), Pakistan under the research grant NRPU-7438.

Funding

Funding was funded by Higher Education Commision, Pakistan, 7438, Asifullah Khan.

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Authors and Affiliations

  1. Department of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan, Khyber Pakhtunkhwa, 23200, Pakistan

    Asad Zia, Sulaiman Shams, Sahib Gul Afridi & Asifullah Khan

  2. Department of Biochemistry, Bahauddin Zakariya University, Multan, Punjab, Pakistan

    Mohibullah Shah

Authors
  1. Asad Zia
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  2. Sulaiman Shams
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  3. Mohibullah Shah
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  4. Sahib Gul Afridi
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  5. Asifullah Khan
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Contributions

A.Z & A.K conceived the basic research idea. A.Z, S.S, and S.G.A contributed to data analyses. A.Z. & M.S prepared the manuscript’s initial draft. A.K finalized the draft and supervised the entire study.

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Correspondence to Asifullah Khan.

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Zia, A., Shams, S., Shah, M. et al. Structural Consequences of IRS-2 nsSNPs and Implication for Insulin Receptor Substrate-2 Protein Stability. Biochem Genet 61, 69–86 (2023). https://doi.org/10.1007/s10528-022-10247-y

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  • DOI: https://doi.org/10.1007/s10528-022-10247-y

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