Neuropilin

Neuropilin
Crystallographic structure of the dimeric B1 domain of human neuropilin 1.
Identifiers
SymbolNRP
PfamPF11980
InterProIPR014648
Membranome16
Available protein structures:
PDB  IPR014648 PF11980 (ECOD; PDBsum)  
AlphaFold
neuropilin 1
Identifiers
SymbolNRP1
NCBI gene8829
HGNC8004
OMIM602069
PDB3I97
RefSeqNM_001024628
UniProtO14786
Other data
LocusChr. 10 p12
Search for
StructuresSwiss-model
DomainsInterPro
neuropilin 2
Identifiers
SymbolNRP2
NCBI gene8828
HGNC8005
OMIM602070
RefSeqNM_201279
UniProtO60462
Other data
LocusChr. 2 q34
Search for
StructuresSwiss-model
DomainsInterPro

Neuropilin is a protein receptor active in neurons.

Types

There are two forms of Neuropilins, NRP-1 and NRP-2.

Subcellular distribution

Although Neuropilins are commonly found at the cell surface, they have also been reported within the mitochondria and nucleus. Both Neuropilin family members can also be found in soluble forms created by alternative splicing or by ectodomain shedding from the cell surface.

Structure

Neuropilins are transmembrane glycoproteins. Neuropilins contain the following four domains:

The structure of B1 domain (coagulation factor 5/8 type) of neuropilin-1 was determined through X-Ray Diffraction with a resolution of 2.90 Å. The secondary structure of this domain is 5% alpha helical and 46% beta sheet.

Function

Neuropilins were first documented to regulate neurogenesis and angiogenesis by complexing with Plexin receptors/class-3 semaphorin ligands and Vascular Endothelial Growth Factor (VEGF) receptors/VEGF ligands, respectively. Neuropilins predominantly act as co-receptors as they have a very small cytoplasmic domain and thus rely upon other cell surface receptors to transduce their signals across a cell membrane. Recent studies have shown that Neuropilins are multifunctional and can partner with a wide variety of transmembrane receptors. Neuropilins are therefore associated with numerous signalling pathways including those activated by Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF), Insulin-like Growth Factor (IGF), Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor beta (TGFβ).

The pleiotropic nature of the NRP receptors results in their involvement in cellular processes, such as axon guidance and angiogenesis, the immune response and remyelination. Therefore, dysregulation of NRP activity has been implicated in many pathological conditions, including many types of cancer and cardiovascular disease.

As a drug target

Neuropilin-1 is a therapeutic target protein in the treatment for leukemia and lymphoma, since It has been shown that there is increased expression in neuropilin-1 in leukemia and lymphoma cell lines. Also, antagonism of neuropilin-1 has been found to inhibit tumour cell migration and adhesion.


References

  1. 1 2 PDB: 3I97​; Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, et al. (March 2010). "Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction". Journal of Medicinal Chemistry. 53 (5): 2215–2226. doi:10.1021/jm901755g. PMC 2841442. PMID 20151671.
  2. ↑ Issitt T, Bosseboeuf E, De Winter N, Dufton N, Gestri G, Senatore V, et al. (January 2019). "Neuropilin-1 Controls Endothelial Homeostasis by Regulating Mitochondrial Function and Iron-Dependent Oxidative Stress". iScience. 11: 205–223. Bibcode:2019iSci...11..205I. doi:10.1016/j.isci.2018.12.005. PMC 6327076. PMID 30623799.
  3. ↑ Mehta V, Fields L, Evans IM, Yamaji M, Pellet-Many C, Jones T, et al. (August 2018). "VEGF (Vascular Endothelial Growth Factor) Induces NRP1 (Neuropilin-1) Cleavage via ADAMs (a Disintegrin and Metalloproteinase) 9 and 10 to Generate Novel Carboxy-Terminal NRP1 Fragments That Regulate Angiogenic Signaling". Arteriosclerosis, Thrombosis, and Vascular Biology. 38 (8): 1845–1858. doi:10.1161/ATVBAHA.118.311118. PMC 6092111. PMID 29880492.
  4. ↑ Rossignol M, Gagnon ML, Klagsbrun M (December 2000). "Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms". Genomics. 70 (2): 211–222. doi:10.1006/geno.2000.6381. PMID 11112349.
  5. ↑ Werneburg S, Buettner FF, Erben L, Mathews M, Neumann H, Mühlenhoff M, et al. (August 2016). "Polysialylation and lipopolysaccharide-induced shedding of E-selectin ligand-1 and neuropilin-2 by microglia and THP-1 macrophages". Glia. 64 (8): 1314–1330. doi:10.1002/glia.23004. PMID 27159043. S2CID 3713077.
  6. 1 2 Pellet-Many C, Frankel P, Jia H, Zachary I (April 2008). "Neuropilins: structure, function and role in disease". The Biochemical Journal. 411 (2): 211–226. doi:10.1042/bj20071639. PMID 18363553.
  7. 1 2 Schwarz Q, Ruhrberg C (January 2010). "Neuropilin, you gotta let me know: should I stay or should I go?". Cell Adhesion & Migration. 4 (1): 61–66. doi:10.4161/cam.4.1.10207. PMC 2852559. PMID 20026901.
  8. 1 2 Kofler N, Simons M (May 2016). "The expanding role of neuropilin: regulation of transforming growth factor-β and platelet-derived growth factor signaling in the vasculature". Current Opinion in Hematology. 23 (3): 260–267. doi:10.1097/moh.0000000000000233. PMC 4957701. PMID 26849476.
  9. ↑ Roy S, Pramanik A, Chakraborti T, Chakraborti S (2017). "Multifaceted Role of Matrix Metalloproteases on Human Diseases". Proteases in Human Diseases. Springer Singapore. pp. 21–40. doi:10.1007/978-981-10-3162-5_2. ISBN 978-981-10-3161-8.
  10. ↑ Mecollari V, Nieuwenhuis B, Verhaagen J (2014). "A perspective on the role of class III semaphorin signaling in central nervous system trauma". Frontiers in Cellular Neuroscience. 8 328. doi:10.3389/fncel.2014.00328. PMC 4209881. PMID 25386118.
  11. ↑ Niland S, Eble JA (February 2019). "Neuropilins in the Context of Tumor Vasculature". International Journal of Molecular Sciences. 20 (3): 639. doi:10.3390/ijms20030639. PMC 6387129. PMID 30717262.
  12. ↑ Pellet-Many C, Mehta V, Fields L, Mahmoud M, Lowe V, Evans I, et al. (November 2015). "Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury". Cardiovascular Research. 108 (2). Oxford University Press: 288–298. doi:10.1093/cvr/cvv229. OCLC 927518632. PMC 4614691. PMID 26410366.
  13. ↑ Harman JL, Sayers J, Chapman C, Pellet-Many C (July 2020). "Emerging Roles for Neuropilin-2 in Cardiovascular Disease". International Journal of Molecular Sciences. 21 (14): 5154. doi:10.3390/ijms21145154. PMC 7404143. PMID 32708258.
  14. ↑ Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, et al. (January 2011). "Targeting neuropilin-1 in human leukemia and lymphoma". Blood. 117 (3): 920–927. doi:10.1182/blood-2010-05-282921. PMC 3298438. PMID 21063027.
  15. ↑ Jia H, Cheng L, Tickner M, Bagherzadeh A, Selwood D, Zachary I (February 2010). "Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity". British Journal of Cancer. 102 (3): 541–552. doi:10.1038/sj.bjc.6605539. PMC 2822953. PMID 20087344.