Neuropilin Functions as an Essential Cell Surface Receptor

Abstract

The Neuropilins (Nrps) are a family of essential cell surface receptors involved in multiple fundamental cellular signaling cascades. Nrp family members have key functions in VEGF-dependent angiogenesis and semaphorin-dependent axon guidance, controlling signaling and cross-talk between these fundamental physiological processes. More recently, Nrp function has been found in diverse signaling and adhesive functions, emphasizing their role as pleiotropic co-receptors. Pathological Nrp function has been shown to be important in aberrant activation of both canonical and alternative pathways. Here we review key recent insights into Nrp function in human health and disease.

Keywords: VEGFR; angiogenesis; heparin-binding protein; neuropilin; protein-protein interaction; receptor structure-function; semaphorin; vascular endothelial growth factor (VEGF).

FIGURE 1.

Structural basis for ligand binding to the Nrp b1 domain. Nrp1 binds to VEGF-A isoforms and Nrp2 binds to proteolytically activated VEGF-C. VEGF-A isoforms are displayed with exons 1 (red), 2–5 (orange), 6a (yellow), 7 (green), 8 (blue), and 9 (pink). The width of the arrows indicates the strength of the interaction. VEGF-C is displayed with the core VEGF homology domain in green, and N- and C-terminal pro-domains are in red and purple, respectively. The proteolytic site in VEGF-C critical for Nrp engagement is represented by a caret. Nrp is displayed as a surface and graphic, adapted from Nrp2 a1a2b1b2 (Protein Data Bank (PDB) = 2QQK) using PyMOL (Schrödinger).

FIGURE 2.

Detailed view of the ligand-binding pocket of Nrp, revealing the basis for specific binding to the conserved C-terminal arginine in ligands. A–C, detail of the binding interface of Nrp1/VEGF-A (PDB = 4DEQ) (A); Nrp2/VEGF-C (PDB = 4QDQ) (B); and Nrp1/Tuftsin (PDB = 2ORZ) (C).

FIGURE 3.

Role of furin processing in regulation of Nrp binding. Semaphorin and viral coat proteins both utilize furin processing (caret) to release a C-terminal arginine, allowing engagement of the b1 domain of Nrp. Semaphorin (PDB = 1OLZ) utilizes a two-site binding mode with the Sema domain engaging the a1 domain of Nrp (42), and the basic C-terminal domain engaging the b1 domain of Nrp with intervening plexin, semaphorin, integrin (PSI), and Ig domains. Viral coat proteins engage the b1 domain of both Nrp and GAGs.

FIGURE 4.

Key areas of research for defining the mechanism of the versatile function of Nrp as a pleiotropic cell surface receptor. Nrp functions in canonical VEGF and semaphorin signaling, binds to unique ligands (including FGF, PDGF, TGF-β1, and hepatocyte growth factor/scatter factor (HGF/SF)), and has important functions as an essential co-receptor in receptor trafficking and function in cis and in trans.