Structure-fluctuation-function relationships of seven pro-angiogenic isoforms of VEGFA, important mediators of tumorigenesis

Francesca Bergantino, Stefano Guariniello, Raffaele Raucci, Giovanni Colonna, Antonella De Luca, Nicola Normanno, Susan Costantini

Research output: Contribution to journalArticle

Abstract

Vascular endothelial growth factor A (VEGFA) has different biological activities and plays a central role in tumor proliferation, angiogenesis and metastasis. Different VEGFA isoforms are generated by alternative splice site selection of exons 6, 7 and 8. In this paper, we analyzed the physical and chemical properties of the VEGFA exon 6 sequence, and modeled the three-dimensional structures of the regions corresponding to exons 6, 7 and 8 of six different pro-angiogenic isoforms of VEGFA in comparison to the experimental structure of VEGFA_165 by a combined approach of fold recognition and comparative modeling strategies and molecular dynamics simulations. Our results showed that i) exon 6 is a very flexible polycation with high disordered propensity, features well conserved in all mammals, ii) the structures of all the isoforms are stabilized by H-bond subnetworks org0anized around HUB residues and, iii) the charge content of exon 6 modulates the intrinsic structural preference of its flexible backbone, which can be described as an ensemble of conformations. Moreover, complexes between NRP-1 and VEGFA isoforms were modeled by molecular docking to study what isoforms are able to bind NRP-1. The analysis of complexes evidenced that VEGFA_121, VEGFA_145, VEGFA_183, VEGFA_189 and VEGFA_206, containing exons 7 and 8a, are able to interact with NRP-1 because they have the key regions of exons 7b and/or 8a. An overviewof the isoforms shows howthe fluctuations are the main guidance of their biological function. MD simulations also provide insights into factors that stabilize the binding regions of isoforms.

Original languageEnglish
Pages (from-to)410-425
Number of pages16
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1854
Issue number5
DOIs
Publication statusPublished - 2015

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Keywords

  • Angiogenesis
  • Cancer
  • Conformational ensemble
  • Molecular dynamics
  • Network analysis
  • VEGFA isoform

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Analytical Chemistry
  • Molecular Biology
  • Medicine(all)

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