Proteopedia - User contributions [en]

Sandbox Reserved 1658

2022-01-19T15:50:25Z

Lisa Elveren:

{{Sandbox_Reserved_ESBS20_}}

<Structure load='2QQM' size='350' frame='true' align='right' caption='Crystal structure of a2b1b2 domains' scene='Insert optional scene name here' />

== Generalities ==

'''Protein :''' Neuropilin-1<br>
'''Gene :''' NRP1<br>
'''Organism :''' Homo sapiens (Human)

<p align="justify">Neuropilin is a 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] which has been highly conserved through evolution (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 44% of similarity<ref name="structural study">PMID: 17989695</ref> by comparing their [https://en.wikipedia.org/wiki/Amino_acid amino acid] sequences. In the human genome, it is located on the [https://en.wikipedia.org/wiki/Chromosome_10 Chromosome 10] and their molar weights fluctuate between 120 and 130 kDa<ref name="structural study"/>.
These proteins are particularly found in the membrane of the endothelial cells but the Neuropilin-1 is involved in several process such as [https://en.wikipedia.org/wiki/Axon axon] guidance during the [https://en.wikipedia.org/wiki/Human_embryonic_development 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>

== Structural highlights ==

<p align="justify">Neuropilin-1 has three different domains<ref name="structural study"/>. A cytoplasmic domain which contains 40 residues, a transmembrane domain which contains 24 residues and a 850-residues 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). It contains, hence two [https://en.wikipedia.org/wiki/CUB_domain CUB domains] (a1/a2), two homologous domains to coagulation factors V/VIII (b1/b2) and a [https://en.wikipedia.org/wiki/MAM_domain 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 [https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/oligomerization 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.<ref name="MAM domain">PMID: 27720589</ref></p>

<p align="justify"> For example, the [https://en.wikipedia.org/wiki/Semaphorin semaphorins] (SEMA) bind to the (a1/a2/b1) domains while Vascular endothelial growth factors (VEGFs) bind to (b1/b2)<ref name="structural study"/>. 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 [https://en.wikipedia.org/wiki/PDZ_domain 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.</p>
<p align="justify">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 <scene name='86/868191/Calcium_binding_site/1'>Calcium binding site</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 an 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 discoidin family members.</p>

== Function ==

<p align="justify">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 [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 cardiovascular development</h5>

<p align="justify">In mature organisms, neuropilins primarily perform the role of pro-angiogenic co-receptors<ref name="cardiovascular development">PMID: 26451046</ref>. 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<ref name="cardiovascular development"/> 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 [https://en.wikipedia.org/wiki/Extracellular_matrix extra-cellular matrix] in endothelial cells.
</p>

<h5>In neural development</h5>

<p align="justify">In [https://en.wikipedia.org/wiki/Nervous_tissue 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.</p>

<h5>In the immune system</h5>

<p align="justify">An 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, 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.</p>

== Disease ==

<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>

== Role in covid contamination ==

<p align="justify">The Neuropilin-1 is one of the entry site of the [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 SARS-CoV-2] in the cells. Indeed autopsies revealed that SARS-CoV-2 infects NRP1-positive cells<ref name="COVID19"/> facing the nasal cavity.
Unlike the SARS-Cov, SARS-CoV-2 is cleaved by a host protease<ref name="COVID19"/> to create the S1-S2 junction in the [https://en.wikipedia.org/wiki/Peplomer 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 <ref name="NRP1 targeting">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</ref>.Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.</p>

== Applications ==

<p align="justify">NRP1 is a unique immune modulator and is investigated as a possible cancer immunotherapy <ref name="therapy">PMID: 24263240</ref> <ref name="NRP1 targeting"/>. 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>

== References ==

<references/>

Sandbox Reserved 1658

2022-01-19T15:43:36Z

Lisa Elveren:

{{Sandbox_Reserved_ESBS20_}}

<Structure load='2QQM' size='350' frame='true' align='right' caption='Crystal structure of a2b1b2 domains' scene='Insert optional scene name here' />

== Generalities ==

'''Protein :''' Neuropilin-1<br>
'''Gene :''' NRP1<br>
'''Organism :''' Homo sapiens (Human)

<p align="justify">Neuropilin is a 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] which has been highly conserved through evolution (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 44% of similarity<ref name="structural study">PMID: 17989695</ref> by comparing their [https://en.wikipedia.org/wiki/Amino_acid amino acid] sequences. In the human genome, it is located on the [https://en.wikipedia.org/wiki/Chromosome_10 Chromosome 10] and their molar weights fluctuate between 120 and 130 kDa<ref name="structural study"/>.
These proteins are particularly found in the membrane of the endothelial cells but the Neuropilin-1 is involved in several process such as [https://en.wikipedia.org/wiki/Axon axon] guidance during the [https://en.wikipedia.org/wiki/Human_embryonic_development 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>

== Structural highlights ==

<p align="justify">Neuropilin-1 has three different domains<ref name="structural study"/>. A cytoplasmic domain which contains 40 residues, a transmembrane domain which contains 24 residues and a 850-residues 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). It contains, hence two [https://en.wikipedia.org/wiki/CUB_domain CUB domains] (a1/a2), two homologous domains to coagulation factors V/VIII (b1/b2) and a [https://en.wikipedia.org/wiki/MAM_domain 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 [https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/oligomerization 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.<ref name="MAM domain">PMID: 27720589</ref></p>

<p align="justify"> For example, the [https://en.wikipedia.org/wiki/Semaphorin semaphorins] (SEMA) bind to the (a1/a2/b1) domains while Vascular endothelial growth factors (VEGFs) bind to (b1/b2)<ref name="structural study"/>. 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 [https://en.wikipedia.org/wiki/PDZ_domain 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.</p>
<p align="justify">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 <scene name='86/868191/Calcium_binding_site/1'>Calcium binding site</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 an 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 discoidin family members.</p>

== Function ==

<p align="justify">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 [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 cardiovascular development</h5>

<p align="justify">In mature organisms, neuropilins primarily perform the role of pro-angiogenic co-receptors<ref name="cardiovascular development">PMID: 26451046</ref>. 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<ref name="cardiovascular development"/> 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 [https://en.wikipedia.org/wiki/Extracellular_matrix extra-cellular matrix] in endothelial cells.
</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>

<h5>In the immune system</h5>

<p align="justify">An 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, 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.</p>

== Disease ==

<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>

== Role in covid contamination ==

<p align="justify">The Neuropilin-1 is one of the entry site of the [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 SARS-CoV-2] in the cells. Indeed autopsies revealed that SARS-CoV-2 infects NRP1-positive cells<ref name="COVID19"/> facing the nasal cavity.
Unlike the SARS-Cov, SARS-CoV-2 is cleaved by a host protease<ref name="COVID19"/> to create the S1-S2 junction in the [https://en.wikipedia.org/wiki/Peplomer 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 <ref name"structur function">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</ref>.Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.</p>

== Applications ==

<p align="justify">NRP1 is a unique immune modulator and is investigated as a possible cancer immunotherapy <ref name="therapy">PMID: 24263240</ref> <ref name"structur function">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</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>

== References ==

<references/>

Sandbox Reserved 1658

2022-01-19T15:40:08Z

Lisa Elveren:

{{Sandbox_Reserved_ESBS20_}}

<Structure load='2QQM' size='350' frame='true' align='right' caption='Crystal structure of a2b1b2 domains' scene='Insert optional scene name here' />

== Generalities ==

'''Protein :''' Neuropilin-1<br>
'''Gene :''' NRP1<br>
'''Organism :''' Homo sapiens (Human)

<p align="justify">Neuropilin is a 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] which has been highly conserved through evolution (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 44% of similarity<ref name="structural study">PMID: 17989695</ref> by comparing their [https://en.wikipedia.org/wiki/Amino_acid amino acid] sequences. In the human genome, it is located on the [https://en.wikipedia.org/wiki/Chromosome_10 Chromosome 10] and their molar weights fluctuate between 120 and 130 kDa<ref name="structural study"/>.
These proteins are particularly found in the membrane of the endothelial cells but the Neuropilin-1 is involved in several process such as [https://en.wikipedia.org/wiki/Axon axon] guidance during the [https://en.wikipedia.org/wiki/Human_embryonic_development 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>

== Structural highlights ==

<p align="justify">Neuropilin-1 has three different domains<ref name="structural study"/>. A cytoplasmic domain which contains 40 residues, a transmembrane domain which contains 24 residues and a 850-residues 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). It contains, hence two [https://en.wikipedia.org/wiki/CUB_domain CUB domains] (a1/a2), two homologous domains to coagulation factors V/VIII (b1/b2) and a [https://en.wikipedia.org/wiki/MAM_domain 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 [https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/oligomerization 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.<ref name="MAM domain">PMID: 27720589</ref></p>

<p align="justify"> For example, the [https://en.wikipedia.org/wiki/Semaphorin semaphorins] (SEMA) bind to the (a1/a2/b1) domains while Vascular endothelial growth factors (VEGFs) bind to (b1/b2)<ref name="structural study"/>. 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 [https://en.wikipedia.org/wiki/PDZ_domain 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.</p>
<p align="justify">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 <scene name='86/868191/Calcium_binding_site/1'>Calcium binding site</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 an 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 discoidin family members.</p>

== Function ==

<p align="justify">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 [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 cardiovascular development</h5>

<p align="justify">In mature organisms, neuropilins primarily perform the role of pro-angiogenic co-receptors<ref name="cardiovascular development">PMID: 26451046</ref>. 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<ref name="cardiovascular development"/> 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 [https://en.wikipedia.org/wiki/Extracellular_matrix extra-cellular matrix] in endothelial cells.
</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>

<h5>In the immune system</h5>

<p align="justify">An 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, 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.</p>

== Disease ==

<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>

== Role in covid contamination ==

<p align="justify">The Neuropilin-1 is one of the entry site of the [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 SARS-CoV-2] in the cells. Indeed autopsies revealed that SARS-CoV-2 infects NRP1-positive cells<ref name="COVID19"/> facing the nasal cavity.
Unlike the SARS-Cov, SARS-CoV-2 is cleaved by a host protease<ref name="COVID19"/> to create the S1-S2 junction in the [https://en.wikipedia.org/wiki/Peplomer 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. Generally NRP receptors facilitate viral entry for several viruses due to their abundance on cells that are exposed to the external environment.Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.</p>

== Applications ==

<p align="justify">NRP1 is a unique immune modulator and is investigated as a possible cancer immunotherapy <ref name="therapy">PMID: 24263240</ref> <ref name"structur function">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</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>

== References ==

<references/>

Sandbox Reserved 1658

2022-01-19T15:40:08Z

Lisa Elveren:

{{Sandbox_Reserved_ESBS20_}}

<Structure load='2QQM' size='350' frame='true' align='right' caption='Crystal structure of a2b1b2 domains' scene='Insert optional scene name here' />

== Generalities ==

'''Protein :''' Neuropilin-1<br>
'''Gene :''' NRP1<br>
'''Organism :''' Homo sapiens (Human)

<p align="justify">Neuropilin is a 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] which has been highly conserved through evolution (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 44% of similarity<ref name="structural study">PMID: 17989695</ref> by comparing their [https://en.wikipedia.org/wiki/Amino_acid amino acid] sequences. In the human genome, it is located on the [https://en.wikipedia.org/wiki/Chromosome_10 Chromosome 10] and their molar weights fluctuate between 120 and 130 kDa<ref name="structural study"/>.
These proteins are particularly found in the membrane of the endothelial cells but the Neuropilin-1 is involved in several process such as [https://en.wikipedia.org/wiki/Axon axon] guidance during the [https://en.wikipedia.org/wiki/Human_embryonic_development 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>

== Structural highlights ==

<p align="justify">Neuropilin-1 has three different domains<ref name="structural study"/>. A cytoplasmic domain which contains 40 residues, a transmembrane domain which contains 24 residues and a 850-residues 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). It contains, hence two [https://en.wikipedia.org/wiki/CUB_domain CUB domains] (a1/a2), two homologous domains to coagulation factors V/VIII (b1/b2) and a [https://en.wikipedia.org/wiki/MAM_domain 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 [https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/oligomerization 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.<ref name="MAM domain">PMID: 27720589</ref></p>

<p align="justify"> For example, the [https://en.wikipedia.org/wiki/Semaphorin semaphorins] (SEMA) bind to the (a1/a2/b1) domains while Vascular endothelial growth factors (VEGFs) bind to (b1/b2)<ref name="structural study"/>. 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 [https://en.wikipedia.org/wiki/PDZ_domain 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.</p>
<p align="justify">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 <scene name='86/868191/Calcium_binding_site/1'>Calcium binding site</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 an 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 [https://en.wikipedia.org/wiki/Discoidin_domain discoidin] family members.</p>

== Function ==

<p align="justify">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 [https://en.wikipedia.org/wiki/Circulatory_system 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 cardiovascular development</h5>

<p align="justify">In mature organisms, neuropilins primarily perform the role of pro-angiogenic co-receptors<ref name="cardiovascular development">PMID: 26451046</ref>. 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<ref name="cardiovascular development"/> 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 [https://en.wikipedia.org/wiki/Extracellular_matrix extra-cellular matrix] in endothelial cells.
</p>

<h5>In neunal development</h5>

<p align="justify">In [https://en.wikipedia.org/wiki/Nervous_tissue 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.</p>

<h5>In the immune system</h5>

<p align="justify">An 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, 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.</p>

== Disease ==

<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>

== Role in covid contamination ==

<p align="justify">The Neuropilin-1 is one of the entry site of the [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 SARS-CoV-2] in the cells. Indeed autopsies revealed that SARS-CoV-2 infects NRP1-positive cells<ref name="COVID19"/> facing the nasal cavity.
Unlike the SARS-Cov, SARS-CoV-2 is cleaved by a host protease<ref name="COVID19"/> to create the S1-S2 junction in the [https://en.wikipedia.org/wiki/Peplomer 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. Generally NRP receptors facilitate viral entry for several viruses due to their abundance on cells that are exposed to the external environment.Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.</p>

== Applications ==

<p align="justify">NRP1 is a unique immune modulator and is investigated as a possible cancer immunotherapy <ref name="therapy">PMID: 24263240</ref> <ref name"structur function">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</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>

== References ==

<references/>