Sandbox Reserved 1658: Difference between revisions
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'''Organism :''' Homo sapiens (Human) | '''Organism :''' Homo sapiens (Human) | ||
<p align="justify">Neuropilin is a [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane protein] which has been highly conserved through evolution. Two different types of Neuropilin have been discovered in vertebrates: Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). They have 44% of similarity 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. | <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. 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 amino acid sequences. In the human genome, it is located on the 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 embryonic development, recognition of the Vascular Endothelial cell Growth Factor ([[VEGF]]) and recognition of covid-19.</p> | 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 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 == | == Structural highlights == | ||
<p align="justify">Neuropilin-1 has three different domains. A cytoplasmic domain which contains 40 residues, a transmembrane domain which contains 24 residues and a 850-residues ectodomain. The latter is an assembly of five individual motifs (a1,a2,b1,b2 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 MAM domain (c). The ligand binding is mediated by the (a1/a2) and (b1/b2) portion of the ectodomain while the c domain mediates Neuripilin oligomerization.</p> | <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,a2,b1,b2 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 Neuripilin 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 semaphorins (SEMA) bind to the (a1/a2/b1) domains while Vascular endothelial growth factors (VEGFs) bind to (b1/b2). The c domain as well as the transmembrane domain, | <p align="justify"> For example, the 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. | <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>. 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)). | 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 <scene name='86/868191/Beta_barrel/1'>beta-barrel</scene> composes of 8 beta-sheets.One part of the domain contains three loops that typically constitute the ligand binding site for discoidin family members.</p> | 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 (290-294, 325-330, 334-342, 354-363, 381-384,391-395,399-411,418-423)<ref name="human neuropilin"/>.One part of the domain contains three loops that typically constitute the ligand binding site for discoidin family members.</p> | ||
== Function == | == Function == | ||
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== Role in covid contamination == | == 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 facing the nasal cavity. | <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 owns a polybasic furin-type cleavage site at 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. Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.</p> | Unlike the SARS-Cov, SARS-CoV-2 owns 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)]. 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. Therefore, Neuropilin-1 facilitates the entry of Sars-Cov-2 in the cells.</p> | ||
== Applications == | == Applications == | ||
