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PDBsum entry 2qqi

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Signaling protein PDB id
2qqi
Jmol
Contents
Protein chain
315 a.a. *
Ligands
GOL
Waters ×282
* Residue conservation analysis
PDB id:
2qqi
Name: Signaling protein
Title: Crystal structure of the b1b2 domains from human neuropilin-
Structure: Neuropilin-1. Chain: a. Fragment: f5/8 typE C 1 and c 2 domains. Synonym: vascular endothelial cell growth factor 165 recept antigen. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nrp1, nrp, vegf165r. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.80Å     R-factor:   0.161     R-free:   0.201
Authors: B.A.Appleton,W.Desmarais,C.Wiesmann
Key ref:
B.A.Appleton et al. (2007). Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J, 26, 4902-4912. PubMed id: 17989695 DOI: 10.1038/sj.emboj.7601906
Date:
26-Jul-07     Release date:   20-Nov-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O14786  (NRP1_HUMAN) -  Neuropilin-1
Seq:
Struc:
 
Seq:
Struc:
923 a.a.
315 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     endothelial cell chemotaxis   7 terms 
  Biochemical function     growth factor binding     3 terms  

 

 
DOI no: 10.1038/sj.emboj.7601906 EMBO J 26:4902-4912 (2007)
PubMed id: 17989695  
 
 
Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding.
B.A.Appleton, P.Wu, J.Maloney, J.Yin, W.C.Liang, S.Stawicki, K.Mortara, K.K.Bowman, J.M.Elliott, W.Desmarais, J.F.Bazan, A.Bagri, M.Tessier-Lavigne, A.W.Koch, Y.Wu, R.J.Watts, C.Wiesmann.
 
  ABSTRACT  
 
Neuropilins (Nrps) are co-receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.
 
  Selected figure(s)  
 
Figure 3.
Figure 3 Overall domain architecture of neuropilins. (A) Domain organization of Nrp2 (blue, a1; green, a2; yellow, b1; red, b2) in complex with the Fab fragment of anti-panNrp^A (tan, heavy chain; gray, light chain). N-glycosylated residues are indicated in magenta. (B) Ribbon representation of the Nrp a2b1b2 structures; the orange spheres highlight a bound calcium ion. (C) Superposition of the Nrp2/Fab complex from two different crystal forms based on the a2b1b2 domains. Note the poor superposition of the a1 domains (yellow arrows) in comparison to the a2b1b2 region (black arrows). Structure figures were produced with PyMol (http://www.pymol.org).
Figure 5.
Figure 5 Features of the Nrp VEGF- and heparin-binding domains. (A) The molecular surface of the rat (PDB code 2ORZ) (Vander Kooi et al, 2007) and human b1b2 crystal structures are colored as described in Figure 4D. Green arrows indicate an acidic groove that is formed by the 'spikes' in the b1 domain (Supplementary Figure S5); this feature forms the Tuftsin-binding site of rat Nrp1. Yellow arrows indicate the approximate location of the heparin-binding patch. (B) The sequence conservation (green, 100%; yellow, than or equal to 75%) of the b1b2 domains among 12 Nrps (Supplementary Figure S3) was mapped onto the surface of the human Nrp1 b1b2 structure. Two highly conserved patches are delineated in red. Residues outlined in cyan indicate those residues that contact the Fab in the anti-Nrp1^B-Fab/b1 complex. The a2 domain (tan) is shown by using a superposition of the b1b2 and a2b1b2 structures from Nrp1. (C) Ribbon representation of the anti-Nrp1^B–Fab/b1 complex (yellow, b1; orange, heavy chain; gray, light chain). (D) The anti-Nrp1^B/b1 interface. The b1 domain is depicted as a molecular surface with a green arrow indicating the Tuftsin/VEGF tail-binding groove. Only CDRs H3 and L1 contact b1.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2007, 26, 4902-4912) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23104057 B.J.Janssen, T.Malinauskas, G.A.Weir, M.Z.Cader, C.Siebold, and E.Y.Jones (2012).
Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex.
  Nat Struct Mol Biol, 19, 1293-1299.
PDB codes: 4gz8 4gz9 4gza
20237569 C.B.Andersen, M.Madsen, T.Storm, S.K.Moestrup, and G.R.Andersen (2010).
Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes.
  Nature, 464, 445-448.
PDB code: 3kq4
19575651 M.Melani, and B.M.Weinstein (2010).
Common factors regulating patterning of the nervous and vascular systems.
  Annu Rev Cell Dev Biol, 26, 639-665.  
20387901 M.W.Parker, L.M.Hellman, P.Xu, M.G.Fried, and C.W.Vander Kooi (2010).
Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin.
  Biochemistry, 49, 4068-4075.  
  20026901 Q.Schwarz, and C.Ruhrberg (2010).
Neuropilin, you gotta let me know: should I stay or should I go?
  Cell Adh Migr, 4, 61-66.  
  20452960 R.H.Adams, and A.Eichmann (2010).
Axon guidance molecules in vascular patterning.
  Cold Spring Harb Perspect Biol, 2, a001875.  
20367445 S.J.Tam, and R.J.Watts (2010).
Connecting vascular and nervous system development: angiogenesis and the blood-brain barrier.
  Annu Rev Neurosci, 33, 379-408.  
19801683 D.Kronenberg, S.Vadon-Le Goff, J.M.Bourhis, B.Font, D.Eichenberger, D.J.Hulmes, and C.Moali (2009).
Strong cooperativity and loose geometry between CUB domains are the basis for procollagen c-proteinase enhancer activity.
  J Biol Chem, 284, 33437-33446.  
19523502 E.R.Schmidt, R.J.Pasterkamp, and L.H.van den Berg (2009).
Axon guidance proteins: novel therapeutic targets for ALS?
  Prog Neurobiol, 88, 286-301.  
20004161 F.Carafoli, D.Bihan, S.Stathopoulos, A.D.Konitsiotis, M.Kvansakul, R.W.Farndale, B.Leitinger, and E.Hohenester (2009).
Crystallographic insight into collagen recognition by discoidin domain receptor 2.
  Structure, 17, 1573-1581.
PDB code: 2wuh
19266292 G.Serini, F.Maione, and F.Bussolino (2009).
Semaphorins and tumor angiogenesis.
  Angiogenesis, 12, 187-193.  
19801203 I.Segura, F.De Smet, P.J.Hohensinner, C.Ruiz de Almodovar, and P.Carmeliet (2009).
The neurovascular link in health and disease: an update.
  Trends Mol Med, 15, 439-451.  
19631637 J.B.Long, S.M.Jay, S.S.Segal, and J.A.Madri (2009).
VEGF-A and Semaphorin3A: modulators of vascular sympathetic innervation.
  Dev Biol, 334, 119-132.  
19200729 M.V.Gelfand, S.Hong, and C.Gu (2009).
Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning.
  Trends Cell Biol, 19, 99.  
18625544 V.A.Potiron, J.Roche, and H.A.Drabkin (2009).
Semaphorins and their receptors in lung cancer.
  Cancer Lett, 273, 1.  
18458115 C.Rolny, L.Capparuccia, A.Casazza, M.Mazzone, A.Vallario, A.Cignetti, E.Medico, P.Carmeliet, P.M.Comoglio, and L.Tamagnone (2008).
The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment.
  J Exp Med, 205, 1155-1171.  
18283547 E.Geretti, A.Shimizu, and M.Klagsbrun (2008).
Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis.
  Angiogenesis, 11, 31-39.  
18664627 H.Kawamura, X.Li, K.Goishi, L.A.van Meeteren, L.Jakobsson, S.Cébe-Suarez, A.Shimizu, D.Edholm, K.Ballmer-Hofer, L.Kjellén, M.Klagsbrun, and L.Claesson-Welsh (2008).
Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization.
  Blood, 112, 3638-3649.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.