In silico screening, genotyping, molecular dynamics simulation and activity studies of SNPs in pyruvate kinase M2

PloS One
Ponnusamy KalaiarasanRameshwar N K Bamezai

Abstract

Role of, 29-non-synonymous, 15-intronic, 3-close to UTR, single nucleotide polymorphisms (SNPs) and 2 mutations of Human Pyruvate Kinase (PK) M2 were investigated by in-silico and in-vitro functional studies. Prediction of deleterious substitutions based on sequence homology and structure based servers, SIFT, PANTHER, SNPs&GO, PhD-SNP, SNAP and PolyPhen, depicted that 19% emerged common between all the mentioned programs. SNPeffect and HOPE showed three substitutions (C31F, Q310P and S437Y) in-silico as deleterious and functionally important. In-vitro activity assays showed C31F and S437Y variants of PKM2 with reduced activity, while Q310P variant was catalytically inactive. The allosteric activation due to binding of fructose 1-6 bisphosphate (FBP) was compromised in case of S437Y nsSNP variant protein. This was corroborated through molecular dynamics (MD) simulation study, which was also carried out in other two variant proteins. The 5 intronic SNPs of PKM2, associated with sporadic breast cancer in a case-control study, when subjected to different computational analyses, indicated that 3 SNPs (rs2856929, rs8192381 and rs8192431) could generate an alternative transcript by influencing splicing factor binding to PKM2. We propo...Continue Reading

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Citations

Apr 4, 2017·Human Mutation·Qifang XuRoland L Dunbrack
Jun 21, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Afreen NaseemM Moshahid Alam Rizvi
Mar 8, 2020·The Journal of Biological Chemistry·Suparno Nandi, Mishtu Dey
Sep 30, 2020·The Journal of Biological Chemistry·Suparno NandiMishtu Dey
Jan 30, 2021·The Journal of Biological Chemistry·Suparno Nandi, Mishtu Dey
Jan 18, 2021·The Journal of Biological Chemistry·Suparno NandiMishtu Dey
Nov 29, 2017·Biochemistry·Dhiraj SrivastavaMishtu Dey
Sep 2, 2021·Journal of Gastrointestinal Cancer·Zafar Iqbal BhatM Moshahid Alam Rizvi

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Methods Mentioned

BETA
genotyping
acetylation

Software Mentioned

GROMACS
FOLDX
Graphing Advanced Computation and Exploration ( GRACE )
SNAP
PolyPhen
SNPeffect
SIFT
GO
HumVar
PolyPhen ( Phenotyping Polymorphism )

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