Assessment of structurally and functionally high-risk nsSNPs impacts on human bone morphogenetic protein receptor type IA (BMPR1A) by computational approach

Md Jahirul Islam; Md Rimon Parves; Shafi Mahmud; Fahmida Alam Tithi; Md Abu Reza

doi:10.1016/j.compbiolchem.2019.03.004

Assessment of structurally and functionally high-risk nsSNPs impacts on human bone morphogenetic protein receptor type IA (BMPR1A) by computational approach

Comput Biol Chem. 2019 Jun:80:31-45. doi: 10.1016/j.compbiolchem.2019.03.004. Epub 2019 Mar 12.

Authors

Md Jahirul Islam¹, Md Rimon Parves², Shafi Mahmud³, Fahmida Alam Tithi², Md Abu Reza³

Affiliations

¹ Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong (USTC), Foy's Lake, Khulshi, 4202, Chittagong, Bangladesh; Division of Computer Aided Drug-Design, The Red-Green Research Center, BICCB, 218 Elephant Road, Dhaka 1205, Bangladesh. Electronic address: jahirjoel87@gmail.com.
² Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong (USTC), Foy's Lake, Khulshi, 4202, Chittagong, Bangladesh.
³ Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh.

PMID: 30884445
DOI: 10.1016/j.compbiolchem.2019.03.004

Abstract

BMPR1A (BMP type 1 receptor) is a transmembrane cell-surface receptor also known as ALK3 (activin-like kinases-3) encodes for a type I serine/threonine kinase receptor and a member of the transforming growth-factor β-receptor (TGF-β) super family. The BMPR1A has a significant interaction with BMP-2 for protein activity and also has a low affinity with growth and differentiation factor 5 (GDF5); positively regulates chondrocyte differentiation. The genetic variations can alter the structure and function of the BMPR1A gene that causes several diseases such as juvenile polyposis syndrome or hereditary cancer-predisposing syndrome. The current study was carried out to identify potential deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in BMPR1A by implementing different computational algorithms such as SIFT, PolyPhen2, SNAP2, PROVEAN, PhD-SNP, SNPs&GO, nsSNPAnalyzer, and P-Mut. From 205 nsSNPs in BMPR1A, 7 nsSNPs (C76Y, C124R, C124Y, C376Y, R443C, R480W, and W487R) were predicted as deleterious in 8 prediction algorithms. The Consurf analysis showed that selected 7 nsSNPs were present in the highly conserved regions. Molecular dynamics simulation analysis also performed to explore conformational changes in the variant structure with respect to its native structure. According to the MDS result, all variants flexibility and rigidity were unbalanced, which may alter the structural and functional behavior of the native protein. Although, three nsSNPs i.e., C124R, C376Y, and R443C have already been reported in patients associated with JPS, but their structural and functional molecular studies remain uncharacterized. Therefore, the findings of this study can provide a better understanding of uncharacterized nsSNPS and to find their association with disease susceptibility and also facilitate to the researchers for designing or developing the target dependent drugs.

Keywords: BMPR1A; Deleterious; JPS; MD simulation; Single nucleotide polymorphism; nsSNPs.

MeSH terms

Algorithms
Amino Acid Sequence
Amino Acid Substitution
Binding Sites / genetics
Bone Morphogenetic Protein Receptors, Type I / genetics*
Computational Biology / methods
Humans
Hydrogen Bonding
Molecular Dynamics Simulation
Mutation, Missense
Polymorphism, Single Nucleotide*
Protein Conformation, alpha-Helical / genetics
Protein Stability
Software

Substances

BMPR1A protein, human
Bone Morphogenetic Protein Receptors, Type I