High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design.

Antonella Paladino,Giorgio Colombo,Laura Belvisi,Monica Civera

doi:10.1371/journal.pcbi.1005334

Antonella Paladino, Giorgio Colombo + Show 2 more

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https://doi.org/10.1371/journal.pcbi.1005334

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Abstract

Understanding how binding events modulate functional motions of multidomain proteins is a major issue in chemical biology. We address several aspects of this problem by analyzing the differential dynamics of αvβ3 integrin bound to wild type (wtFN10, agonist) or high affinity (hFN10, antagonist) mutants of fibronectin. We compare the dynamics of complexes from large-scale domain motions to inter-residue coordinated fluctuations to characterize the distinctive traits of conformational evolution and shed light on the determinants of differential αvβ3 activation induced by different FN sequences. We propose an allosteric model for ligand-based integrin modulation: the conserved integrin binding pocket anchors the ligand, while different residues on the two FN10’s act as the drivers that reorganize relevant interaction networks, guiding the shift towards inactive (hFN10-bound) or active states (wtFN10-bound). We discuss the implications of results for the design of integrin inhibitors.

Highlights

Integrins are heterodimeric cell adhesion receptors, composed by the association of α and β subunits
We address several aspects of this problem by analyzing the differential dynamics of αvβ3 integrin bound to wild type or high affinity mutants of fibronectin
We have concentrated on the multidomain receptor αvβ3 integrin bound to two different sequences of the endogenous ligand fibronectin: the wild type one, wtFN10, which acts as an agonist activating the receptor, and a high affinity mutant, hFN10, which acts as a true antagonist inhibiting the receptor

Summary

Introduction

Integrins are heterodimeric cell adhesion receptors, composed by the association of α and β subunits They are typically characterized by a bilobular head and two legs that span the plasma membrane. [1,2] Conformational changes from the bent to the open structures in integrin extracellular, transmembrane and cytoplasmic domains underlie a diverse range of biological processes, including cell migration, morphogenesis, immune responses, vascular haemostasis, cell-to-cell interaction and intracellular signal transduction. The dysregulation of these processes contributes to the pathogenesis of many diseases. The RGD sequence of physiologic ligands typically engages αvβ in a cleft between the β-propeller and βA domains, producing a characteristic electrostatic clamp between the guanidinium moiety of the RGD-triad and aspartic acids of the αv subunit and, at the same time, enabling RGD-Asp(Oδ1/Oδ2) to coordinate a metal ion at MIDAS (Metal Ion-Dependent Adhesion Site) of the β3 subunit (Fig 1b and 1c). [9]

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