Neuropilin Structure

Domains

NRPs are glycoproteins with a relatively large extracellular domain (860 amino acids), a transmembrane domain, and a relatively short cytoplasmic domain of about 40 amino acids. The extracellular domain consists of five subdomains, which are referred to as a1, a2, b1, b2, and c. The a1a2 and b1b2 domains are involved in ligand binding and cell adhesion. The c domain is thought to function as a site for homo-or hetero-dimerization of NRP1 and NRP2. The function of the short cytoplasmic domain, which is highly conserved, is not clear. A neuropilin interacting protein (NIP) has been identified that contains a PDZ domain. It binds to the C-terminal three amino acids of NRP1 (S-E-A-COOH).

In addition to full-length NRPs, some cell types express truncated NRP isoforms. These naturally occurring proteins contain only the a1a2 and b1b2 subdomains, are soluble, and are secreted by cells. The soluble NRP molecules are produced by premature truncation within introns and as a result are characterized by having intron-derived 3' nucleotides and C-terminal amino acid sequences.

Neuropilin Binding Sites for Ligands

NRPs can bind multiple ligands, which can be categorized into three groupings: the class 3 semaphorins, the VEGF family, and various transmembrane proteins. Sema-phorins have a sema domain that binds to the NRP a1a2

domain and an Ig-basic C-terminal domain that binds to the b1b2 domain. VEGF family members bind NRPs with a high degree of specificity. Placental growth factor-2 (PlGF-2), VEGF-B, and VEGF-E bind NRP1 but not NRP2. On the other hand, VEGF145 and VEGF-C bind NRP2 but not NRP1. Domain binding sites have been determined for VEGF165 and PlGF-2, both of which bind to the b1b2 domain. The binding sites of VEGF-B, VEGF-C, and VEGF-E on NRP have not been determined.

Heparin, which enhances both VEGF165 and PlGF-2 binding to NRP1, binds the b1b2 domain. Heparin and heparan sulfate may play a critical role in EC NRP function by forming a complex of VEGF165 or PlGF-2, NRP1b1b2, and heparin that facilitates ligand binding to NRP1. Because the b1b2 domain is a binding site for Sema3A, VEGF165, and PlGF-2, there may be a structural basis for competitive inhibition of the different NRP1 ligands. For example, Sema3A competes VEGF165-induced EC migration and VEGF165 inhibits Sema3A-induced growth cone collapse, suggesting overlapping binding sites in the b1b2 domain.

The third category of NRP1 ligands are transmembrane proteins, including plexins A, L1, VEGFR-1, VEGFR-2, and heparan sulfate proteoglycans (HSPG). These bind to the NRP1 extracellular domain, but the subdomains involved have not yet been determined.

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