Neuropilin

Neuropilin is a protein receptor active in neurons.

Neuropilin
Crystallographic structure of the dimeric B1 domain of human neuropilin 1.[1]
Identifiers
SymbolNRP
InterProIPR014648
Membranome16
neuropilin 1
Identifiers
SymbolNRP1
NCBI gene8829
HGNC8004
OMIM602069
PDB3I97
RefSeqNM_001024628
UniProtO14786
Other data
LocusChr. 10 p12
neuropilin 2
Identifiers
SymbolNRP2
NCBI gene8828
HGNC8005
OMIM602070
RefSeqNM_201279
UniProtO60462
Other data
LocusChr. 2 q34

There are two forms of Neuropilins, NRP-1 and NRP-2. Neuropilins are transmembrane glycoproteins, 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. [2][3] 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. [2][3] 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). [4][5] Both Neuropilin family members can also be found in soluble forms created by alternative splicing or by ectodomain shedding from the cell surface. [6][7]

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.[8] Therefore, dysregulation of NRP activity has been implicated in many pathological conditions, including many types of cancer and cardiovascular disease. [9][10][11]

Applications

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.[12] Also, antagonism of neuropilin-1 has been found to inhibit tumour cell migration and adhesion.[13]

Structure

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.[1]

Ramachandran plot.[14]

References
  1. 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): 2215–26. doi:10.1021/jm901755g. PMC 2841442. PMID 20151671.
  2. Pellet-Many C, Frankel P, Jia H, Zachary I (April 2008). "Neuropilins: structure, function and role in disease". The Biochemical Journal. 411 (2): 211–26. doi:10.1042/bj20071639. PMID 18363553.
  3. Schwarz Q, Ruhrberg C (January 2010). "Neuropilin, you gotta let me know: should I stay or should I go?". Cell Adhesion & Migration. 4 (1): 61–6. doi:10.4161/cam.4.1.10207. PMC 2852559. PMID 20026901.
  4. 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): 260–7. doi:10.1097/moh.0000000000000233. PMC 4957701. PMID 26849476.
  5. Roy, Soumitra; Pramanik, Asmita; Chakraborti, Tapati; Chakraborti, Sajal (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
  6. 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): 211–22. doi:10.1006/geno.2000.6381. PMID 11112349.
  7. Werneburg S, Buettner FF, Erben L, Mathews M, Neumann H, Mühlenhoff M, Hildebrandt H (August 2016). "Polysialylation and lipopolysaccharide-induced shedding of E-selectin ligand-1 and neuropilin-2 by microglia and THP-1 macrophages". Glia. 64 (8): 1314–30. doi:10.1002/glia.23004. PMID 27159043.
  8. 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.
  9. 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.
  10. 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): 260–7. doi:10.1097/MOH.0000000000000233. PMC 4957701. PMID 26849476.
  11. 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. Oxford University Press. 108 (2): 288–98. doi:10.1093/cvr/cvv229. OCLC 927518632. PMC 4614691. PMID 26410366.
  12. 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): 920–7. doi:10.1182/blood-2010-05-282921. PMC 3298438. PMID 21063027.
  13. 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): 541–52. doi:10.1038/sj.bjc.6605539. PMC 2822953. PMID 20087344.
  14. "MolProbity Ramachandran analysis of PDB structure 3I97" (PDF). www.pdb.org.
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