Abstract
Neuropilin‐2 is a transmembrane receptor involved in lymphangiogenesis and neuronal development. In adults, neuropilin‐2 and its homologous protein neuropilin‐1 have been implicated in cancers and infection. Molecular determinants of the ligand selectivity of neuropilins are poorly understood. We have identified and structurally characterized a zinc ion binding site on human neuropilin‐2. The neuropilin‐2‐specific zinc ion binding site is located near the interface between domains b1 and b2 in the ectopic region of the protein, remote from the neuropilin binding site for its physiological ligand, i.e. vascular endothelial growth factor. We also present an X‐ray crystal structure of the neuropilin‐2 b1 domain in a complex with the C‐terminal sub‐domain of VEGF‐A. Zn2+ binding to neuropilin‐2 destabilizes the protein structure but this effect was counteracted by heparin, suggesting that modifications by glycans and zinc in the extracellular matrix may affect functional neuropilin‐2 ligand binding and signalling activity.
Highlights
Neuropilin-2 (NRP2) and neuropilin-1 (NRP1) are homologous transmembrane receptors that are expressed in diverse tissues, sharing a common domain organization and 44% amino acid sequence identity in humans [1,2,3]
We have reported the first crystal structure of a complex between the peptide corresponding to the C-terminus of vascular endothelial growth factor (VEGF)-A165 and the b1 domain of NRP2
The level of structural similarity is somewhat surprising given that NRP1 and NRP2 have distinct physiological preferences for the growth factors, with VEGF-A165 being the main NRP1 ligand, and VEGF-C signalling primarily through NRP2
Summary
Neuropilin-2 (NRP2) and neuropilin-1 (NRP1) are homologous transmembrane receptors that are expressed in diverse tissues, sharing a common domain organization and 44% amino acid sequence identity in humans [1,2,3]. Both NRPs have essential roles in the control of axonal homing in the developing nervous system, as revealed by the phenotypes of genetically deficient mice [4,5,6,7]. We describe the three-dimensional structure of a molecular complex between the C-terminal region of VEGF-A165 and the b1 ligand binding domain of NRP2, further addressing the question of ligand selectivity
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