Sandbox Reserved 1658

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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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spinqualitylabelsall models Crystal structure of the b1/b2 domains Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

spinqualitylabelsall models Crystal structure of a2b1b2 domains Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Generalities 2 Structural highlights 3 Function 3.1 In cardiovascular development 3.2 In neuronal development 4 Disease 5 Relevance 6 Role in covid contamination 7 Applications 8 References

Generalities

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

Neuropilin is a 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. 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.

Structural highlights

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 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.

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, are involved in the receptor dimerization. The cytoplasmic domain does not contain a binding domain but a PDZ segment and 3 amino acids (serine, glutamic acid and alanine). This segment 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 . 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)). On an other side, b1 and b2 form a jellyroll 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 (growth of new blood vessels from pre-existing ones) 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. 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 binding. Researchers also think that neuropilins affect the vascular motility of endothelial cells, independently of their action on the protein complex VEGF/VEGFR.

In neuronal development

In neuronal tissues, NRP1 associate with semaphoring-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.

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. It would stimulate migration, invasion and tumorigenesis.

Relevance

Role in covid contamination

Applications

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References