VEGFA, B, C: implications of the C-terminal sequence variations for the interaction with neuropilins

DOI: 10.3390/biom12030372

Authors: Charles Eldrid (University College London (UCL)) , Mire Zloh (University College London; University Business Academy (Serbia)) , Constantina Fotinou (University College London) , Tamas Yelland (University College London) , Lefan Yu (University College London) , Filipa Mota (University College London) , David L. Selwood (University College London) , Snezana Djordjevic (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biomolecules , VOL 12

State: Published (Approved)
Published: February 2022

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.

Journal Keywords: X-ray crystallography; ligand-binding protein; neuropilin; SPR; molecular dynamics

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 04/03/2022 08:26

Documents:
biomolecules-12-00372.pdf

Discipline Tags:

Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)