Investigating the Effect of Cancer-Related Mutations on the Structure and Function of Integrin αVβ3 Heterodimers through Molecular Dynamics Simulations

Abstract

Metastasis is the tightly regulated development of secondary growths from a primary tumor site, and represents the biggest challenge in the treatment of cancer. Metastasis requires several proteins working in concert to proceed, and among the primary proteins that govern its progression are the integrins. The integrins are heterodimeric cell surface proteins that serve as the major adhesion molecules in mammalian cells. They are known to control cell-cell as well as cell-ECM interactions, and regulate bidirectional signaling in cells. Integrins are frequently dysregulated or mutated in cancer, where they transduce extracellular cues from the tumor microenvironment, leading to changes in cell shape, motility, survival, proliferation, and angiogenesis. While the mechanisms underlying differential integrin expression in invasive tumors is well-characterized, the role of integrin mutagenesis in cancer progression remains largely unknown. This study thus aims to characterize three mutations in the integrin αV subtype: G50T, G188T, and G252A. These mutants were obtained from mutational screens in cancer patients, as deposited in the CoSMiC database. Molecular models for the ITGAV mutants were generated through SPDB v4.10 based on published integrin αV crystal structure (PDBID 1JV2). The models were equilibrated through GROMACS v4.6.7 prior to analyses. Protein docking between integrin αV subunit and its heterodimeric pair, integrin β3, was performed through ClusPro 2.0. This revealed altered heterodimer formation in mutant αV-β3 structures compared to the wild type. Analysis of intermolecular interactions in the generated heterodimers showed diminished salt bridges in the mutants relative to the wild type. In particular, G188TαV experienced the greatest decrease in salt bridge content (50% salt bridge loss). Molecular dynamics simulations are currently underway to determine and compare the binding strengths between each αV-β3 dimeric pair.