%0 Generic %A Santhiya, P. %A Bharathi, A. Christian %A Ibrahim, B. Syed %D 2019 %T The pathogenicity, structural and functional exploration of human HMGB1 single nucleotide polymorphisms using in silico study %U https://tandf.figshare.com/articles/dataset/The_pathogenicity_structural_and_functional_exploration_of_human_HMGB1_single_nucleotide_polymorphisms_using_i_in_silico_i_study/10001789 %R 10.6084/m9.figshare.10001789.v2 %2 https://tandf.figshare.com/ndownloader/files/18154811 %K HMGB1 %K mutagenesis %K supervised learning %K non-synonymous mutation %K SNP %X
The human HMGB1 gene mutations have a major impact on several immune-related diseases and cancer. The detrimental effect of non-synonymous mutations of HMGB1 has not been investigated yet, hence the present study aims to examine single nucleotide polymorphisms and their implications on the structure-function of human HMGB1. The multifaceted HMGB1 protein acts as pleiotropic cytokine and regulates essential genes for coordinated cellular functions. The mutational effect on HMGB1 was analyzed by sequence-based homology methods, supervised learning methods, and structure-based methods. The study identified 58 non-synonymous mutations in human HMGB1, out of which only 2 mutations; R10T (rs61742222) and F103C (rs61733675) were classified as the SNPs with highest deleterious and disease-causing mutants. The effect of these mutations in structure of HMGB1 was scrutinized and the R10T mutant found to have a distinct structural behaviour in the B-box domain. In addition, R10T mutant predicted that it affects the MoRF function of HMGB1 and it could disrupt the DNA binding or/and protein partner interaction activity by HMGB1. F103C mutation takes place at the TLR binding and cytokine inducing region of HMGB1, hence it could affect the protein binding activity which involves in many cellular signaling. The study identified potent mutations R10T (a cancer-causing somatic mutation) and F103C (a novel mutation) and these mutations either directly or indirectly hinder DNA binding activity and TLR and cytokine binding of HMGB1. These findings will help in understanding the molecular basis of these promising mutations and functional role of human HMGB1 in cancer and immunological diseases.
AbbreviationsAGER
Advanced glycosylation end product-specific receptor
CXCLChemokine (C-X-C motif) ligand
dbSNPThe single nucleotide polymorphism database
HMGB1High mobility group box 1
LINCSLINear Constraint Solver
MDSMolecular dynamics simulation
MoRFMolecular recognition features
NPTNumber of particle, Pressure and Temperature
NVTNumber of particle, Volume and Temperature
nsSNPNon-synonymous SNP
PBCPartial boundary condition
PCAPrincipal component analysis
PMEPartial mesh Ewald
RMSDRoot mean square deviation
RMSFRoot mean square fluctuation
SNPSingle nucleotide polymorphism
SPCSingle-point charge
TLRToll-like receptor
UTRUn-translated Region
Advanced glycosylation end product-specific receptor
Chemokine (C-X-C motif) ligand
The single nucleotide polymorphism database
High mobility group box 1
LINear Constraint Solver
Molecular dynamics simulation
Molecular recognition features
Number of particle, Pressure and Temperature
Number of particle, Volume and Temperature
Non-synonymous SNP
Partial boundary condition
Principal component analysis
Partial mesh Ewald
Root mean square deviation
Root mean square fluctuation
Single nucleotide polymorphism
Single-point charge
Toll-like receptor
Un-translated Region
Communicated by Ramaswamy H. Sarma
%I Taylor & Francis