title: A novel kinase mutation in VEGFR-1 predisposes its αC-helix/activation loop towards allosteric activation: Atomic insights from protein simulation.
abstract: Vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in diverse pathologies, including cancers. Although VEGFR-1 is considered as functionally impaired kinase, its decoy characteristics make it an important regulator of VEGFR-mediated signaling, particularly in tumor angiogenesis. VEGFR-1 conveys signaling via its tyrosine kinase (TK) domain whose activation is regulated by phosphorylation of specific tyrosine residues. Thus dysregulation of VEGFR-1 signaling, as reported in most of the cancers, might be a consequence of altered phosphorylation that could be attributed to genotypic variations in its TK domain. Considering the importance of TK domain of VEGFR-1, we carried out its mutational screening in 84 clinically validated and histopathologically confirmed colorectal cancer patients. By means of direct DNA sequencing and SNP analyses, eight novel variations, including one synonymous, two deletion, one missense and four intronic variations, were reported in the TK domain of VEGFR-1. rs730882263:C>G variation specifically reported in colon cancer, representing a single-atomic change (Sulfur to Oxygen) in the predicted (p.Cys1110Ser) protein, was observed as potentially deleterious variation as assessed by multiple single-nucleotide polymorphism prediction servers. Molecular dynamics simulations of VEGFR-1 Wt and (p.Cys1110Ser) variant models revealed major conformational changes in variant protein presumptuously generating an open conformation thereby exposing the activation domain and consequently increasing the probability of phosphorylation events: a condition frequently reported in cancers.
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.
authors.forename: Taseem A
authors.identifier: 0000-0001-8903-9662
authors.initials: TA
authors.lastname: Mokhdomi
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.|Molecular Reproduction, Development and Genetics Laboratory, Indian Institute of Science, Bangalore, India.
authors.forename: Shoiab
authors.initials: S
authors.lastname: Bukhari
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.
authors.forename: Naveed Anjum
authors.identifier: 0000-0002-5977-0531
authors.initials: NA
authors.lastname: Chikan
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.
authors.forename: Asif
authors.initials: A
authors.lastname: Amin
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.
authors.forename: Asrar H
authors.initials: AH
authors.lastname: Wafai
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.
authors.forename: Sajad H
authors.initials: SH
authors.lastname: Wani
authors.affiliation: Department of General Surgery, Sher-i-Kashmir Institute of Medical Sciences, Srinagar (J and K), India.
authors.forename: Nisar A
authors.initials: NA
authors.lastname: Chowdri
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), India.
authors.forename: Raies A
authors.initials: RA
authors.lastname: Qadri
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D000072756:Protein Conformation, alpha-Helical; D011499:Protein Processing, Post-Translational; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D040281:Vascular Endothelial Growth Factor Receptor-1