Mokhdomi, Taseem A and Bukhari, Shoiab and Chikan, Naveed Anjum and Amin, Asif and Wafai, Asrar H and Wani, Sajad H and Chowdri, Nisar A and Qadri, Raies A (2016) A novel kinase mutation in VEGFR-1 predisposes its alpha C-helix/activation loop towards allosteric activation: Atomic insights from protein simulation. In: EUROPEAN JOURNAL OF HUMAN GENETICS, 24 (9). pp. 1287-1293.
Full text not available from this repository. (Request a copy)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.
| Item Type: | Journal Article |
|---|---|
| Publication: | EUROPEAN JOURNAL OF HUMAN GENETICS |
| Additional Information: | Copy right for this article belongs to the NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Department/Centre: | Division of Biological Sciences > Molecular Reproduction, Development & Genetics |
| Date Deposited: | 07 Dec 2016 07:20 |
| Last Modified: | 07 Dec 2016 07:20 |
| URI: | http://eprints.iisc.ac.in/id/eprint/55004 |
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