Sandbox Reserved 1658: Difference between revisions

<p align="justify">Neuropilin is a highly conserved type I <ref name"structur function">Fumio Nakamura and Yoshio Goshima Bookshelf ID: NBK6408 https://www.ncbi.nlm.nih.gov/books/NBK6408/</ref> [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane protein] (see image on the right, determined by [https://consurfdb.tau.ac.il/ ConSurfDB]).[[Image:Structure evolution data.png | thumb]][[Image:Color scale2QQM evolution.png | thumb]]

Two different types of Neuropilin have been discovered in vertebrates: Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). They have a similarity of 44 % between their amino acid sequences<ref name="structural study">PMID: 17989695</ref>. In the human genome, Neuropilin-1 is located on chromosome 10, with the molar weight fluctuating between 120 and 130 kDa<ref name="structural study"/>.

Neuropilins are prominently found in the membrane of endothelial cells, but Neuropilin-1 is additionally involved in several processes such as [https://en.wikipedia.org/wiki/Axon axon] guidance during the embryonic development, recognition of the Vascular Endothelial Cell Growth Factor ([[VEGF]]) and recognition of COVID-19<ref name="COVID19">DOI: 10.1126/science.abd2985 </ref>.</p>

== Structure ==

<p align="justify">Neuropilin-1 has three different domains<ref name="structural study"/>: a cytoplasmic domain containing 40 residues, a transmembrane domain containing 24 residues, and a 850 residue ectodomain<ref name="human neuropilin">Christian C. Lee, Andreas Kreusch,Daniel McMullan, Ken Ng, and Glen Spraggon Crystal Structure of the HumanNeuropilin-1 b1 Domain https://www.cell.com/structure/pdf/S0969-2126(02)00941-3.pdf</ref>. The latter is an assembly of five individual motifs (a1, <scene name='86/868191/Domaine_a2/1'>a2</scene>, <scene name='86/868191/Domaine_b1/1'>b1</scene>, <scene name='86/868191/Domaine_b2/1'>b2</scene> and c). These can be further subdivided into the [https://en.wikipedia.org/wiki/CUB_domain CUB domains] (a1 and a2), two homologous domains to coagulation factors V/VIII (b1 and b2) and a [https://en.wikipedia.org/wiki/MAM_domain MAM domain] (c). Ligand binding is mediated by the CUB domains and the (b1/b2) portion of the ectodomain while the c domain mediates Neuropilin oligomerization. However, the c domain is not able to independently facilitate multimerization of NRP molecules. It has therefore been hypothesized to contribute to the assembly and regulation of the signaling complexes by positionning the other extracellular domains of Neuropilin-1 away from the membrane.<ref name="MAM domain">PMID: 27720589</ref></p>

<p align="justify"> As an example, the semaphorins (SEMA) bind to the CUB domains and b1 while vascular endothelial growth factors (VEGFs) bind to b1 and b2 <ref name="structural study"/>. The c domain, as well as the transmembrane domain, is involved in receptor dimerization. The cytoplasmic domain contains a [https://en.wikipedia.org/wiki/PDZ_domain PDZ domain] rather than a binding site. This segment is only 42-44 amino acids length and has no catalytic function. It participates in the formation and stimulation of signalling complexes.</p>

<p align="justify">It has been determined that the interactions between b1 and b2, as well as between a2 and b1/b2 are the same for Neuropilin 1 and 2. However, the interactions between a1 and the other domains are not yet fully understood.

The a1 and a2 domains contain <scene name='86/868191/Calcium_binding_site/1'>Calcium binding sites</scene><ref name="structural study"/>. The ion is coordinated by two carbonyl oxygens from Ala(252)and Ile(253) and by three negatively charged side chains: (Glu(195), Asp(209) and Asp(250))<ref name="structural study"/>.  

On the other side, b1 and b2 form a jellyroll<ref name="structural study"/> <scene name='86/868191/Beta_barrel/1'>beta-barrel</scene> composes of 8 beta-sheets (<scene name='86/868191/Fin/1'>290-294 (violet), 325-330 (green), 334-342 (red), 354-363 (blue), 381-384 (orange), 391-395 (cyan), 399-411 (brown), 418-423 (white)</scene>).One part of the domain contains three loops that typically constitute the ligand binding site for members of the Discoidin domain family.</p>

<p align="justify">Neuropilins are involved in several signaling pathways. They act mainly as co-receptors because of their small cytoplasmic domain, and therefore associate with other receptors to transduce their signals through a cell membrane. Neuropilin-1 is involved in the development of the cardiovascular system, but also in [https://en.wikipedia.org/wiki/Angiogenesis angiogenesis] and [https://en.wikipedia.org/wiki/Organogenesis organogenesis]. It is also involved in the development of some neuronal circuits.</p>

<h5>In neuronal development</h5>

<p align="justify">In neuronal tissues, NRP1 associates with semaphorin-3A to perform growth cone guidance. It helps guiding axonal growth during the development of the nervous system by mediating the chemorepulsant activity of semaphorin.</p>

<p align="justify">Expression of NRP1 has been detected in several cells of the immune system<ref name="immunity>DOI 10.3389/fimmu.2017.01228</ref> such as macrophages, dendritic cells, as well as in T cell subsets. In dendritic cells and T cells subsets, NRP1 helps to trigger the immune response. It has also been hypothesized that NRP1 could represent a new activation marker for T cells. NRP1 is particularly involved in the interaction between T cells and dendritic cells. It is also involved in the removal mechanism of T cells and in the transmission mechanism of immunoregulatory effects of semasphorin-3A on T cells.</p>

<p align="justify">Since neuropilins are involved in the development of the neuronal and cardiovascular system, abnormalities in these genes lead to abnormalities in cardiac, vascular and nervous development. A dysregulation of the activity of neuropilins is involved in many pathologies, such as cancers and cardiovascular diseases. Indeed, neuropilins stimulate many functions that increase tumor aggression such as immune tolerance or cell proliferation. For example, overexpression of NRP1 has been detected in many cancers, including leukemia, lymphoma and melanoma<ref name="maladie">DOI 10.1002/path.2989</ref>. It would stimulate migration, invasion and tumorigenesis. The role of NRP1 as a mediator of tumor development has been investigated and many observations show that overexpression of NRP1 is also involved in colon<ref name="colon">PMID: 15161648</ref> cancer, breast cancer, lung cancer and glioma.</p>

<p align="justify">Neuropilin-1 is one of the entry sites of the [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 SARS-CoV-2] in cells. Autopsies have shown SARS-CoV-2 to infect NRP1-positive cells<ref name="COVID19"/> facing the nasal cavity.

Unlike SARS-Cov, SARS-CoV-2 contains a polybasic furin-type cleavage site<ref name="COVID19"/> at the S1-S2 junction in the [https://en.wikipedia.org/wiki/Peplomer spike protein(S)]. Previously it had already been known that NRP1 binds [[furin]]-cleaved substrates. The cleavage of the spike protein causes the formation of a C-terminal motif which observes the Cend rule. This motif is responsible for the binding of the virus on the b1 domain of NRP1. Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in cells.</p>

<p align="justify">NRP1 targeting is investigated as a possible cancer therapy <ref name="therapy">PMID: 24263240</ref>. Several methods have been developed to inhibit the oncogenic activities of NRP1 by using iRNA <ref name="applications">DOI 10.3892/etm.2018.6234</ref>, monoclonal antibodies or even peptides. Especially, monoclonal antibodies are experimented as antitumor agents. Some have already being developed such as specific CUB antibodies<ref name="applications"/> and anti-NRP1B<ref name="applications"/> that inhibit cell migration induced by VEGF and the formation of tumors in endothelial cells.</p>