4deq
Structure of the Neuropilin-1/VEGF-A complex
Structural highlights
DiseaseVEGFA_HUMAN Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:603933. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. FunctionNRP1_HUMAN The membrane-bound isoform 1 is a receptor involved in the development of the cardiovascular system, in angiogenesis, in the formation of certain neuronal circuits and in organogenesis outside the nervous system. It mediates the chemorepulsant activity of semaphorins. It binds to semaphorin 3A, The PLGF-2 isoform of PGF, The VEGF-165 isoform of VEGF and VEGF-B. Coexpression with KDR results in increased VEGF-165 binding to KDR as well as increased chemotaxis. It may regulate VEGF-induced angiogenesis. The soluble isoform 2 binds VEGF-165 and appears to inhibit its binding to cells. It may also induce apoptosis by sequestering VEGF-165. May bind as well various members of the semaphorin family. Its expression has an averse effect on blood vessel number and integrity.VEGFA_HUMAN Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.[1] [2] [3] Publication Abstract from PubMedNeuropilin-1 (Nrp1) is an essential receptor for angiogenesis that binds to VEGF-A. Nrp1 directly binds 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 seven encoded region of VEGF-A and function as an isoform specific receptor for VEGF-A164/5. Recent data has implicated exon eight encoded residues, which are found in all pro-angiogenic VEGF-A isoforms, in Nrp binding. We have determined the crystal structure of the exon 7/8 encoded VEGF-A heparin binding domain (HBD) in complex with the Nrp1 b1 domain. This structure clearly demonstrates that residues from both exon seven and eight physically contribute to Nrp1 binding. Using an in vitro binding assay, we have determined the relative contributions of exon seven and eight encoded residues. We demonstrate that the exon eight encoded C-terminal arginine is essential for the interaction of VEGF-A with Nrp1 and mediates high-affinity Nrp binding. Exon seven encoded electronegative residues make additional interactions with the L1 loop of Nrp1. While otherwise conserved, the primary sequence of Nrp1 and Nrp2 differ significantly in this region. We further show that VEGF-A164 binds fifty-fold more strongly to Nrp1 than Nrp2. Direct repulsion between the electronegative exon seven encoded residues of the HBD 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-A164 to Nrp1. Structural basis for the selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1.,Parker MW, Xu P, Li X, Vander Kooi CW J Biol Chem. 2012 Feb 7. PMID:22318724[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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