Sandbox Reserved 1658

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== Disease ==
== Disease ==
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<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 [https://en.wikipedia.org/wiki/Cardiovascular_disease cardiovascular diseases]. Indeed, neuropilins stimulate many functions that increase tumor aggression such as [https://en.wikipedia.org/wiki/Immune_tolerance immune tolerance] or [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation]. For example, overexpression of NRP1 has been detected in many cancers, including [https://en.wikipedia.org/wiki/Leukemia leukemia], [https://en.wikipedia.org/wiki/Lymphoma lymphoma] and [https://en.wikipedia.org/wiki/Melanoma 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>
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<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 [https://en.wikipedia.org/wiki/Cardiovascular_disease cardiovascular diseases]. Indeed, neuropilins stimulate many functions that increase tumor aggression such as [https://en.wikipedia.org/wiki/Immune_tolerance immune tolerance] or [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation]. For example, overexpression of NRP1 has been detected in many cancers, including [https://en.wikipedia.org/wiki/Leukemia leukemia], [https://en.wikipedia.org/wiki/Lymphoma lymphoma] and [https://en.wikipedia.org/wiki/Melanoma melanoma]<ref name="maladie">DOI 10.1002/path.2989</ref>. It would stimulate migration, invasion and [https://en.wikipedia.org/wiki/Carcinogenesis 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>
== Role in covid contamination ==
== Role in covid contamination ==

Revision as of 16:37, 19 January 2022

This Sandbox is Reserved from 26/11/2020, through 26/11/2021 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1643 through Sandbox Reserved 1664.
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Crystal structure of a2b1b2 domains

Drag the structure with the mouse to rotate

Contents

Generalities

Protein : Neuropilin-1
Gene : NRP1
Organism : Homo sapiens (Human)

Neuropilin is a type I [1] transmembrane protein which has been highly conserved through evolution (see image on the right, determined by ConSurfDB).

Two different types of Neuropilin have been discovered in vertebrates: Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). They have 44% of similarity[2] by comparing their amino acid sequences. In the human genome, it is located on the Chromosome 10 and their molar weights fluctuate between 120 and 130 kDa[2].

These proteins are particularly found in the membrane of the endothelial cells but the Neuropilin-1 is involved in several process such as axon guidance during the embryonic development, recognition of the Vascular Endothelial cell Growth Factor (VEGF) and recognition of covid-19[3].

Structural highlights

Neuropilin-1 has three different domains[2]. A cytoplasmic domain which contains 40 residues, a transmembrane domain which contains 24 residues and a 850-residues ectodomain[4]. The latter is an assembly of five individual motifs (a1,,, and c). It contains, hence two CUB domains (a1/a2), two homologous domains to coagulation factors V/VIII (b1/b2) and a MAM domain (c). The ligand binding is mediated by the (a1/a2) and (b1/b2) portion of the ectodomain while the c domain mediates Neuropilin oligomerization. However MAM domain isn't able to support on its own multimerization of NRP molecules. So, it might contribute to the assembly and regulation of the signaling complexes by positionning the other extracellular domains of NRPs away from the membrane.[5]

For example, the semaphorins (SEMA) bind to the (a1/a2/b1) domains while Vascular endothelial growth factors (VEGFs) bind to (b1/b2)[2]. The c domain as well as the transmembrane domain, is involved in the receptor dimerization. The cytoplasmic domain does not contain a binding domain but a PDZ domain. This segment is only 42-44 amino acids length and by the way hasn't any catalytic function. It participates in the formation and stimulation of signalling complexes.

In 2007, a study has demonstrated that the interactions between b1 and b2, and between a2 and (b1/b2) are the same for Neuropilin 1 and 2. However a1 interacts differently with the other domains and these interactions are still not really understood. The a1 and a2 domains are CUB domains and include [2]. 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))[2]. On an other side, b1 and b2 form a jellyroll[2] composes of 8 beta-sheets ().One part of the domain contains three loops that typically constitute the ligand binding site for discoidin family members.

Function

Neuropilins are involved in many 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 angiogenesis and organogenesis. It is also involved in the development of some neuronal circuits.

In cardiovascular development

In mature organisms, neuropilins primarily perform the role of pro-angiogenic co-receptors[6]. Neuropilin-1 works as a specific co-receptor of VEGFR-2 for VEGF-A. After binding and activation, neuropilins promote angiogenesis by stabilizing the VEGF/VEGFR[6] binding. Researchers also think that neuropilins affect the vascular motility of endothelial cells, independently of their action on the protein complex VEGF/VEGFR. Besides, NRP1 enhances the signalling of the extra-cellular matrix in endothelial cells.

In neural development

In neural 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.

In the immune system

An expression of NRP1 has been detected in several cells of the immune system[7] such as macrophages, dendritic cells, but also in T cell subsets. In dendritic cells and T cells subsets, NRP1 helps to trigger the immune response. Researchers also think that NRP1 could represent a new activation marker for T cells. Especially, NRP1 is 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.

Disease

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[8]. 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[9] cancer, breast cancer, lung cancer and glioma.

Role in covid contamination

The Neuropilin-1 is one of the entry site of the SARS-CoV-2 in the cells. Indeed autopsies revealed that SARS-CoV-2 infects NRP1-positive cells[3] facing the nasal cavity. Unlike the SARS-Cov, SARS-CoV-2 is cleaved by a host protease[3] to create the S1-S2 junction in the spike protein(S). Or it was already 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. In general, NRP receptors facilitate viral entry for several viruses due to their abundance on cells exposed to an external environment [10].Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.

Applications

NRP1 is a unique immune modulator and is investigated as a possible cancer immunotherapy [11] [10]. Several methods have been developed to inhibit the oncogenic activities of NRP1 by using iRNA [12], monoclonal antibodies or even peptides. Especially, monoclonal antibodies are experimented as antitumor agents. Some have already being developed such as specific CUB antibodies[12] and anti-NRP1B[12] that inhibit cell migration induced by VEGF and the formation of tumors in endothelial cells.

References

  1. ↑ Fumio Nakamura and Yoshio Goshima Bookshelf ID: NBK6408 https://www.ncbi.nlm.nih.gov/books/NBK6408/
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Appleton BA, Wu P, Maloney J, Yin J, Liang WC, Stawicki S, Mortara K, Bowman KK, Elliott JM, Desmarais W, Bazan JF, Bagri A, Tessier-Lavigne M, Koch AW, Wu Y, Watts RJ, Wiesmann C. Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J. 2007 Nov 28;26(23):4902-12. Epub 2007 Nov 8. PMID:17989695
  3. ↑ 3.0 3.1 3.2 Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M, Smura T, Levanov L, Szirovicza L, Tobi A, Kallio-Kokko H, Osterlund P, Joensuu M, Meunier FA, Butcher SJ, Winkler MS, Mollenhauer B, Helenius A, Gokce O, Teesalu T, Hepojoki J, Vapalahti O, Stadelmann C, Balistreri G, Simons M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020 Nov 13;370(6518):856-860. doi: 10.1126/science.abd2985. Epub 2020, Oct 20. PMID:33082293 doi:http://dx.doi.org/10.1126/science.abd2985
  4. ↑ 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
  5. ↑ Yelland T, Djordjevic S. Crystal Structure of the Neuropilin-1 MAM Domain: Completing the Neuropilin-1 Ectodomain Picture. Structure. 2016 Oct 3. pii: S0969-2126(16)30267-2. doi:, 10.1016/j.str.2016.08.017. PMID:27720589 doi:http://dx.doi.org/10.1016/j.str.2016.08.017
  6. ↑ 6.0 6.1 Guo HF, Vander Kooi CW. Neuropilin Functions as an Essential Cell Surface Receptor. J Biol Chem. 2015 Dec 4;290(49):29120-6. doi: 10.1074/jbc.R115.687327. Epub 2015 , Oct 8. PMID:26451046 doi:http://dx.doi.org/10.1074/jbc.R115.687327
  7. ↑ Roy S, Bag AK, Singh RK, Talmadge JE, Batra SK, Datta K. Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy. Front Immunol. 2017 Oct 10;8:1228. doi: 10.3389/fimmu.2017.01228. eCollection, 2017. PMID:29067024 doi:http://dx.doi.org/10.3389/fimmu.2017.01228
  8. ↑ Jubb AM, Strickland LA, Liu SD, Mak J, Schmidt M, Koeppen H. Neuropilin-1 expression in cancer and development. J Pathol. 2012 Jan;226(1):50-60. doi: 10.1002/path.2989. Epub 2011 Oct 25. PMID:22025255 doi:http://dx.doi.org/10.1002/path.2989
  9. ↑ Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M, Ellis LM. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol. 2004 Jun;164(6):2139-51. doi: 10.1016/S0002-9440(10)63772-8. PMID:15161648 doi:http://dx.doi.org/10.1016/S0002-9440(10)63772-8
  10. ↑ 10.0 10.1 Neuropilin-1 : a checkpoint target with unique implications for cancer immunology and immunotherapy. (s. d.). Journal for ImmunoTherapy of Cancer. https://jitc.bmj.com/content/8/2/e000967
  11. ↑ Chaudhary B, Khaled YS, Ammori BJ, Elkord E. Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother. 2014 Feb;63(2):81-99. doi: 10.1007/s00262-013-1500-0. , Epub 2013 Nov 22. PMID:24263240 doi:http://dx.doi.org/10.1007/s00262-013-1500-0
  12. ↑ 12.0 12.1 12.2 Ding Y, Zhou J, Wang S, Li Y, Mi Y, Gao S, Xu Y, Chen Y, Yan J. Anti-neuropilin-1 monoclonal antibody suppresses the migration and invasion of human gastric cancer cells via Akt dephosphorylation. Exp Ther Med. 2018 Aug;16(2):537-546. doi: 10.3892/etm.2018.6234. Epub 2018 May, 30. PMID:30116312 doi:http://dx.doi.org/10.3892/etm.2018.6234
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