Crystal Structure of the Neuropilin-1 MAM Domain: Completing the Neuropilin-1 Ectodomain Picture

Abstract

SummaryNeuropilins (NRPs) are single-pass transmembrane receptors involved in several signaling pathways that regulate key physiological processes such as vascular morphogenesis and axon guidance. The MAM domain of NRP, which has previously been implicated in receptor multimerization, was the only portion of the ectopic domain of the NRPs for which the structure, until now, has been elusive. Using site-directed mutagenesis in the linker region preceding the MAM domain we generated a protein construct amenable to crystallization. Here we present the crystal structure of the MAM domain of human NRP1 at 2.24 Å resolution. The protein exhibits a jellyroll topology, with Ca2+ ions bound at the inter-strand space enhancing the thermostability of the domain. We show that the MAM domain of NRP1 is monomeric in solution and insufficient to drive receptor dimerization, which leads us to propose a different role for this domain in the context of NRP membrane assembly and signaling.

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“…Neuropilins 1 and 2 (NRP1 and NRP2) act as nonenzymatic co‐receptors of VEGFR2 and VEGFR3, respectively (W. Ye, ). Neuropilins have a large extracellular domain, a transmembrane domain, and a short intracellular domain without catalytic activity (Yelland & Djordjevic, ). Binding of VEGF ligands to their specific receptors leads to dimerization of receptors and signal transduction for their biological effects (Hashemi Goradel et al, ).…”

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“…In addition, NP1 are found primarily in arterial endothelium and is a receptor for semaphorins 3A, 3C, 3F while NP2 is highly expressed and localized in venous and lymphatic endothelium and binds to BB, 3C, 3D and 3F of the class three semaphorins [15][16][17][18]. The semaphorins are members of a family of axons or guidance molecules that signal by interaction with transmembrane receptor complexes that incorporate neuropilins, as co-receptors to plexins which are major receptors for all semaphorin family members [19][20][21]. NP1 interacts with VEGF A, B, E and platelet growth factor (PGF) whereas NP2 interact with VEGF A, B, C, and D [19,22].…”

“…The semaphorins are members of a family of axons or guidance molecules that signal by interaction with transmembrane receptor complexes that incorporate neuropilins, as co-receptors to plexins which are major receptors for all semaphorin family members [19][20][21]. NP1 interacts with VEGF A, B, E and platelet growth factor (PGF) whereas NP2 interact with VEGF A, B, C, and D [19,22]. Generally, Neuropilins contain the following four domains:…”

“…Neuropilins are high affinity receptors for semaphorin 3 family [8,19,25,26,27,28]. Only class three semaphorins out of the existing eight classes bind to neuropilins (i.e.…”

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“…2). 71 The recent publication of the crystal structure of the MAM domain may provide interesting information to optimize docking of peptides in this crucial domain 72 . Another interesting approach designed a peptide with a motif recognizing the VEGF binding domain of Neuropilin-1 73 .…”