Structural basis for the selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1

Journal Article · Wed Jul 25 04:00:00 EDT 2012 · J. Biol. Chem.

DOI:https://doi.org/10.1074/jbc.M111.331140· OSTI ID:1038599

Parker, Matthew W; Xu, Ping; Li, Xiaobo; Vander Kooi, Craig W ^[1]

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1. Kentucky

Neuropilin-1 (Nrp1) is an essential receptor for angiogenesis that binds to VEGF-A. Nrp1 binds directly to VEGF-A with high affinity, but the nature of their selective binding has remained unclear. Nrp1 was initially reported to bind to the exon 7-encoded region of VEGF-A and function as an isoform-specific receptor for VEGF-A164/165. Recent data have implicated exon 8-encoded residues, which are found in all proangiogenic VEGF-A isoforms, in Nrp binding. We have determined the crystal structure of the exon 7/8-encoded VEGF-A heparin binding domain in complex with the Nrp1-b1 domain. This structure clearly demonstrates that residues from both exons 7 and 8 physically contribute to Nrp1 binding. Using an in vitro binding assay, we have determined the relative contributions of exon 7- and 8-encoded residues. We demonstrate that the exon 8-encoded C-terminal arginine is essential for the interaction of VEGF-A with Nrp1 and mediates high affinity Nrp binding. Exon 7-encoded electronegative residues make additional interactions with the L1 loop of Nrp1. Although otherwise conserved, the primary sequences of Nrp1 and Nrp2 differ significantly in this region. We further show that VEGF-A{sub 164} binds 50-fold more strongly to Nrp1 than Nrp2. Direct repulsion between the electronegative exon 7-encoded residues of the heparin binding domain and the electronegative L1 loop found only in Nrp2 is found to significantly contribute to the observed selectivity. The results reveal the basis for the potent and selective binding of VEGF-A{sub 164} to Nrp1.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: OTHERNIHOTHER U.S. STATES
• OSTI ID: 1038599
• Journal Information: J. Biol. Chem., Journal Name: J. Biol. Chem. Journal Issue: (10) ; 03, 2012 Vol. 287; ISSN JBCHA3; ISSN 0021-9258
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AFFINITY
ANGIOGENESIS
ARGININE
CRYSTAL STRUCTURE
CRYSTALLOGRAPHY
EXONS
GROWTH FACTORS
HEPARIN
IN VITRO
PROTEIN STRUCTURE
RESIDUES