VEGFA, B, C: Implications of the C-Terminal Sequence Variations for the Interaction with Neuropilins.

Charles Eldrid,Constantina Fotinou,Mire Zloh,Snezana Djordjevic,Tamas Yelland,David L Selwood,Lefan Yu,Filipa Mota

doi:10.3390/biom12030372

Abstract

Vascular endothelial growth factors (VEGFs) are the key regulators of blood and lymphatic vessels’ formation and function. Each of the proteins from the homologous family VEGFA, VEGFB, VEGFC and VEGFD employs a core cysteine-knot structural domain for the specific interaction with one or more of the cognate tyrosine kinase receptors. Additional diversity is exhibited by the involvement of neuropilins–transmembrane co-receptors, whose b1 domain contains the binding site for the C-terminal sequence of VEGFs. Although all relevant isoforms of VEGFs that interact with neuropilins contain the required C-terminal Arg residue, there is selectivity of neuropilins and VEGF receptors for the VEGF proteins, which is reflected in the physiological roles that they mediate. To decipher the contribution made by the C-terminal sequences of the individual VEGF proteins to that functional differentiation, we determined structures of molecular complexes of neuropilins and VEGF-derived peptides and examined binding interactions for all neuropilin-VEGF pairs experimentally and computationally. While X-ray crystal structures and ligand-binding experiments highlighted similarities between the ligands, the molecular dynamics simulations uncovered conformational preferences of VEGF-derived peptides beyond the C-terminal arginine that contribute to the ligand selectivity of neuropilins. The implications for the design of the selective antagonists of neuropilins’ functions are discussed.

Highlights

Publisher’s Note: MDPI stays neutralNeuropilin-1 (NRP1) and neuropilin-2 (NRP2) are single-pass transmembrane proteins with approximately 840 amino acid residues in their extracellular domain and a small intracellular region containing 44 residues [1,2]
While the ectopic region, comprising five structural domains, interacts with a range of physiological ligands, the intracellular region is devoid of any catalytic activity, and studies show distinct roles for the cytoplasmic peptide [3,4], neuropilins are not viewed as canonical functional receptors
We examined a series of peptides corresponding to the C-terminal ends of the subset of physiological ligands for neuropilins

Summary

Introduction

Publisher’s Note: MDPI stays neutralNeuropilin-1 (NRP1) and neuropilin-2 (NRP2) are single-pass transmembrane proteins with approximately 840 amino acid residues in their extracellular (ectopic) domain and a small intracellular region containing 44 residues [1,2]. The role of these proteins is commonly described as that of co-receptors, since many of their physiological functions are tightly linked to supporting the activities of other wellcharacterised receptors, such as several transmembrane tyrosine kinases and plexins [1,5]. Since their discovery as the receptors for class 3 semaphorins, neuropilins were shown to be involved in binding a range of other ligands including vascular endothelial growth factors, TGF-beta, hepatocyte growth factor, galectins and several viral proteins [5–9]. In mammals there are four VEGF genes designated with regard to jurisdictional claims in published maps and institutional affiliations

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Results

Conclusion