In:
Frontiers in Molecular Biosciences, Frontiers Media SA, Vol. 9 ( 2022-4-28)
Abstract:
T Cell Immune Regulator 1, ATPase H + Transporting V0 Subunit A3 (TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H + -ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Single amino acid changes in highly conserved areas of the TCIRG1 protein have been linked to autosomal recessive osteopetrosis and severe congenital neutropenia. We used multiple computational approaches to classify disease-prone single nucleotide polymorphisms (SNPs) in TCIRG1. We used molecular dynamics analysis to identify the deleterious nsSNPs, build mutant protein structures, and assess the impact of mutation. Our results show that fifteen nsSNPs (rs199902030, rs200149541, rs372499913, rs267605221, rs374941368, rs375717418, rs80008675, rs149792489, rs116675104, rs121908250, rs121908251, rs121908251, rs149792489 and rs116675104) variants are likely to be highly deleterious mutations as by incorporating them into wild protein they destabilize the wild protein structure and function. They are also located in the V-ATPase I domain, which may destabilize the structure and impair TCIRG1 protein activation, as well as reduce its ATPase effectiveness. These mutants have not yet been identified in patients suffering from CN and osteopetrosis while (G405R, R444L, and D517N) reported in our study are already associated with osteopetrosis. Mutation V52L reported in our study was identified in a patient suspected for CN. Finally, these mutants can help to further understand the broad pool of illness susceptibilities associated with TCIRG1 catalytic kinase domain activation and aid in the development of an effective treatment for associated diseases.
Type of Medium:
Online Resource
ISSN:
2296-889X
DOI:
10.3389/fmolb.2022.879875
DOI:
10.3389/fmolb.2022.879875.s001
DOI:
10.3389/fmolb.2022.879875.s002
DOI:
10.3389/fmolb.2022.879875.s003
DOI:
10.3389/fmolb.2022.879875.s004
DOI:
10.3389/fmolb.2022.879875.s005
DOI:
10.3389/fmolb.2022.879875.s006
DOI:
10.3389/fmolb.2022.879875.s007
DOI:
10.3389/fmolb.2022.879875.s008
DOI:
10.3389/fmolb.2022.879875.s009
DOI:
10.3389/fmolb.2022.879875.s010
DOI:
10.3389/fmolb.2022.879875.s011
DOI:
10.3389/fmolb.2022.879875.s012
DOI:
10.3389/fmolb.2022.879875.s013
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2814330-9
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