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Impact of single amino acid substitution on the structure and function of TANK‐binding kinase‐1
Author(s) -
Umair Mohd,
Khan Shama,
Mohammad Taj,
Shafie Alaa,
Anjum Farah,
Islam Asimul,
Hassan Md. Imtaiyaz
Publication year - 2021
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.30070
Subject(s) - tank binding kinase 1 , protein kinase domain , serine , kinase , amino acid , threonine , biology , mutation , neurodegeneration , phosphorylation , biochemistry , protein kinase a , chemistry , cancer research , medicine , disease , gene , map kinase kinase kinase , pathology , mutant
Abstract Tank‐binding kinase 1 (TBK1) is a serine/threonine protein kinase involved in various signaling pathways and subsequently regulates cell proliferation, apoptosis, autophagy, antiviral and antitumor immunity. Dysfunction of TBK1 can cause many complex diseases, including autoimmunity, neurodegeneration, and cancer. This dysfunction of TBK1 may result from single amino acid substitutions and subsequent structural alterations. This study analyzed the effect of substituting amino acids on TBK1 structure, function, and subsequent disease using advanced computational methods and various tools. In the initial assessment, a total of 467 mutations were found to be deleterious. After that, in detailed structural and sequential analyses, 13 mutations were found to be pathogenic. Finally, based on the functional importance, two variants (K38D and S172A) of the TBK1 kinase domain were selected and studied in detail by utilizing all‐atom molecular dynamics (MD) simulation for 200 ns. MD simulation, including correlation matrix and principal component analysis, helps to get deeper insights into the TBK1 structure at the atomic level. We observed a substantial change in variants' conformation, which may be possible for structural alteration and subsequent TBK1 dysfunction. However, substitution S172A shows a significant conformational change in TBK1 structure as compared to K38D. Thus, this study provides a structural basis to understand the effect of mutations on the kinase domain of TBK1 and its function associated with disease progression.