PDBsum entry 1q47

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Signaling protein PDB id
Protein chains
484 a.a. *
NAG ×4
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Structure of the semaphorin 3a receptor-binding module
Structure: Semaphorin 3a. Chain: a, b. Fragment: sema-3a 65k (residues 26-520). Synonym: semaphorin iii, sema iii, semaphorin d, sema d. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Biol. unit: Dimer (from PQS)
2.80Å     R-factor:   0.249     R-free:   0.294
Authors: A.Antipenko,J-P.Himanen,K.Van Leyen,V.Nardi-Dei,J.Lesniak,W. K.R.Rajashankar,M.Lu,C.Hoemme,A.Puschel,D.Nikolov
Key ref:
A.Antipenko et al. (2003). Structure of the semaphorin-3A receptor binding module. Neuron, 39, 589-598. PubMed id: 12925274 DOI: 10.1016/S0896-6273(03)00502-6
01-Aug-03     Release date:   03-Aug-04    
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Protein chains
Pfam   ArchSchema ?
O08665  (SEM3A_MOUSE) -  Semaphorin-3A
772 a.a.
484 a.a.
Key:    PfamA domain  Secondary structure  CATH domain


DOI no: 10.1016/S0896-6273(03)00502-6 Neuron 39:589-598 (2003)
PubMed id: 12925274  
Structure of the semaphorin-3A receptor binding module.
A.Antipenko, J.P.Himanen, K.van Leyen, V.Nardi-Dei, J.Lesniak, W.A.Barton, K.R.Rajashankar, M.Lu, C.Hoemme, A.W.Püschel, D.B.Nikolov.
The semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. Their distinctive feature is a conserved 500 amino acid semaphorin domain, a ligand-receptor interaction module also present in plexins and scatter-factor receptors. We report the crystal structure of a secreted 65 kDa form of Semaphorin-3A (Sema3A), containing the full semaphorin domain. Unexpectedly, the semaphorin fold is a variation of the beta propeller topology. Analysis of the Sema3A structure and structure-based mutagenesis data identify the neuropilin binding site and suggest a potential plexin interaction site. Based on the structure, we present a model for the initiation of semaphorin signaling and discuss potential similarities with the signaling mechanisms of other beta propeller cell surface receptors, such as integrins and the LDL receptor.
  Selected figure(s)  
Figure 2.
Figure 2. Sema3A-65K Forms Noncovalent Dimers in the Absence of Nrp-1 and Undergoes Dimer-to-Monomer Transition to Bind Nrp-1 with 1:1 Stoichiometry(A) Two orthogonal stereoviews of the Sema3A-65K dimer in the asymmetric unit of the crystals. One of the monomers is in green, the other in blue.(B–D) Sedimentation equilibrium studies of Sema3A-65K and Nrp-1 demonstrate that they associate to form 1:1 heterodimers. Shown are 30 μM samples of Sema3A-65K (B), Nrp-1AB (C), and Sema3A-65K/Nrp-1AB (D). The data fits best a single species with a molecular weight of 122 kDa for Sema3A-65K (the protein is a dimer), 64 kDa for Nrp-1AB, and 117 kDa for Sema3A-65K/Nrp-1AB.(E) Sema3A-Δ1 and Sema3A-Δ2, unlike Sema3A-65K, are monomeric in solutions.
Figure 5.
Figure 5. Model for Semaphorin Signaling(A) Initiation of Sema3A-mediated signaling via the Nrp-1/Plexin-A1 complex (see discussion in text). Sema3A is in magenta (Sema domain, heptagon; PSI domain, circle; Ig domain, oval). In plexin, the Sema domain is in dark blue, the IPT domains in green, and the PSI regions in light blue. The intracellular Sex-Plexin domain is in brown, and the star corresponds to the activated form (the red arrow indicates signaling directing growth cone collapse). In Nrp-1, the A1 and A2 domains are in red, B1 and B2 are in orange, and the MAM domain is in yellow. Sema3A binding results in a 2:2:2 ligand/receptor/coreceptor complex formation and the release of the plexin membrane-proximal extracellular region, which in the absence of constrains adopts an active conformation (right panel).(B) (Left panel) Initiation of Sema4D signaling via the Plexin-B1 receptor. In this case, no coreceptors are required. As with Sema3A, ligand binding disrupts the inhibitory semaphorin conformation, resulting in activation of downstream signaling. (Middle panel) The LDL receptor and plexins share a structurally similar autoinhibition mechanism. In both cases, the β propeller domains (heptagons) function as an alternate substrate and bind in cis other domains of the receptors, thus inhibiting the molecules. The inhibition of the LDLR is relieved at high pH, allowing the β propeller domain to be displaced by LDL. (Right panel) Integrin activation. The α subunit is in blue, and the β is in red. The large conformational change in plexins that accompanies the release of autoinhibition is reminiscent of the rearrangement of integrin ectodomains during activation. Interestingly, integrins have also been shown to undergo an intracellular domain separation (brown arrow) concomitant with receptor activation (Kim et al., 2003). In addition, plexins and integrins may share inside-out signaling.
  The above figures are reprinted by permission from Cell Press: Neuron (2003, 39, 589-598) copyright 2003.  
  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
20877282 B.J.Janssen, R.A.Robinson, F.Pérez-Brangulí, C.H.Bell, K.J.Mitchell, C.Siebold, and E.Y.Jones (2010).
Structural basis of semaphorin-plexin signalling.
  Nature, 467, 1118-1122.
PDB codes: 3okt 3okw 3oky 3ol2
20727575 H.Liu, Z.S.Juo, A.H.Shim, P.J.Focia, X.Chen, K.C.Garcia, and X.He (2010).
Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1.
  Cell, 142, 749-761.
PDB codes: 3nvn 3nvq 3nvx
20410128 J.Merte, Q.Wang, C.W.Vander Kooi, S.Sarsfield, D.J.Leahy, A.L.Kolodkin, and D.D.Ginty (2010).
A forward genetic screen in mice identifies Sema3A(K108N), which binds to neuropilin-1 but cannot signal.
  J Neurosci, 30, 5767-5775.  
20051117 S.K.Tolofari, S.M.Richardson, A.J.Freemont, and J.A.Hoyland (2010).
Expression of semaphorin 3A and its receptors in the human intervertebral disc: potential role in regulating neural ingrowth in the degenerate intervertebral disc.
  Arthritis Res Ther, 12, R1.  
20881961 T.Nogi, N.Yasui, E.Mihara, Y.Matsunaga, M.Noda, N.Yamashita, T.Toyofuku, S.Uchiyama, Y.Goshima, A.Kumanogoh, and J.Takagi (2010).
Structural basis for semaphorin signalling through the plexin receptor.
  Nature, 467, 1123-1127.
PDB codes: 3afc 3al8 3al9
18625544 V.A.Potiron, J.Roche, and H.A.Drabkin (2009).
Semaphorins and their receptors in lung cancer.
  Cancer Lett, 273, 1.  
19843518 Y.Tong, P.K.Hota, J.Y.Penachioni, M.B.Hamaneh, S.Kim, R.S.Alviani, L.Shen, H.He, W.Tempel, L.Tamagnone, H.W.Park, and M.Buck (2009).
Structure and function of the intracellular region of the plexin-b1 transmembrane receptor.
  J Biol Chem, 284, 35962-35972.
PDB code: 3hm6
18443147 J.J.Song, J.D.Garlick, and R.E.Kingston (2008).
Structural basis of histone H4 recognition by p55.
  Genes Dev, 22, 1313-1318.
PDB codes: 3c99 3c9c
18045991 L.Roth, C.Nasarre, S.Dirrig-Grosch, D.Aunis, G.Crémel, P.Hubert, and D.Bagnard (2008).
Transmembrane domain interactions control biological functions of neuropilin-1.
  Mol Biol Cell, 19, 646-654.  
18587441 N.E.Barrett, L.Holbrook, S.Jones, W.J.Kaiser, L.A.Moraes, R.Rana, T.Sage, R.G.Stanley, K.L.Tucker, B.Wright, and J.M.Gibbins (2008).
Future innovations in anti-platelet therapies.
  Br J Pharmacol, 154, 918-939.  
17207242 A.Seltsam, S.Strigens, C.Levene, V.Yahalom, M.Moulds, J.J.Moulds, H.Hustinx, V.Weisbach, D.Figueroa, C.Bade-Doeding, D.S.DeLuca, and R.Blasczyk (2007).
The molecular diversity of Sema7A, the semaphorin that carries the JMH blood group antigens.
  Transfusion, 47, 133-146.  
17989695 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, and C.Wiesmann (2007).
Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding.
  EMBO J, 26, 4902-4912.
PDB codes: 2qqi 2qqj 2qqk 2qql 2qqm 2qqn 2qqo
18024597 O.G.Wong, T.Nitkunan, I.Oinuma, C.Zhou, V.Blanc, R.S.Brown, S.R.Bott, J.Nariculam, G.Box, P.Munson, J.Constantinou, M.R.Feneley, H.Klocker, S.A.Eccles, M.Negishi, A.Freeman, J.R.Masters, and M.Williamson (2007).
Plexin-B1 mutations in prostate cancer.
  Proc Natl Acad Sci U S A, 104, 19040-19045.  
17916560 Y.Tong, P.Chugha, P.K.Hota, R.S.Alviani, M.Li, W.Tempel, L.Shen, H.W.Park, and M.Buck (2007).
Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain.
  J Biol Chem, 282, 37215-37224.
PDB code: 2r2o
15557320 A.P.Mould, M.A.Travis, S.J.Barton, J.A.Hamilton, J.A.Askari, S.E.Craig, P.R.Macdonald, R.A.Kammerer, P.A.Buckley, and M.J.Humphries (2005).
Evidence that monoclonal antibodies directed against the integrin beta subunit plexin/semaphorin/integrin domain stimulate function by inducing receptor extension.
  J Biol Chem, 280, 4238-4246.  
16122393 C.Hartwig, A.Veske, S.Krejcova, G.Rosenberger, and U.Finckh (2005).
Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin.
  BMC Neurosci, 6, 53.  
16275925 C.Siebold, N.Berrow, T.S.Walter, K.Harlos, R.J.Owens, D.I.Stuart, J.R.Terman, A.L.Kolodkin, R.J.Pasterkamp, and E.Y.Jones (2005).
High-resolution structure of the catalytic region of MICAL (molecule interacting with CasL), a multidomain flavoenzyme-signaling molecule.
  Proc Natl Acad Sci U S A, 102, 16836-16841.
PDB codes: 2bry 2c4c
16314868 R.P.Kruger, J.Aurandt, and K.L.Guan (2005).
Semaphorins command cells to move.
  Nat Rev Mol Cell Biol, 6, 789-800.  
15642257 Y.Tong, D.Hughes, L.Placanica, and M.Buck (2005).
When monomers are preferred: a strategy for the identification and disruption of weakly oligomerized proteins.
  Structure, 13, 7.  
15210733 J.M.Swiercz, R.Kuner, and S.Offermanns (2004).
Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2.
  J Cell Biol, 165, 869-880.  
15167892 J.Stamos, R.A.Lazarus, X.Yao, D.Kirchhofer, and C.Wiesmann (2004).
Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor.
  EMBO J, 23, 2325-2335.
PDB code: 1shy
15060572 L.Tamagnone, and P.M.Comoglio (2004).
To move or not to move? Semaphorin signalling in cell migration.
  EMBO Rep, 5, 356-361.  
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.