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PDBsum entry 2vj3

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protein metals links
Transcription PDB id
2vj3
Jmol
Contents
Protein chain
120 a.a. *
Metals
_CL ×2
_CA ×4
_NA ×2
Waters ×23
* Residue conservation analysis
PDB id:
2vj3
Name: Transcription
Title: Human notch-1 egfs 11-13
Structure: Neurogenic locus notch homolog protein 1. Chain: a. Fragment: egfs 11-13, residues 411-526. Synonym: notch 1, hn1, translocation-associated notch protein tan-1, notch-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.60Å     R-factor:   0.239     R-free:   0.244
Authors: S.Johnson,J.Cordle,J.Z.Tay,P.Roversi,S.M.Lea
Key ref:
J.Cordle et al. (2008). A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat Struct Biol, 15, 849-857. PubMed id: 18660822 DOI: 10.1038/nsmb.1457
Date:
06-Dec-07     Release date:   29-Jul-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P46531  (NOTC1_HUMAN) -  Neurogenic locus notch homolog protein 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
2555 a.a.
120 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     calcium ion binding     1 term  

 

 
DOI no: 10.1038/nsmb.1457 Nat Struct Biol 15:849-857 (2008)
PubMed id: 18660822  
 
 
A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.
J.Cordle, S.Johnson, J.Z.Tay, P.Roversi, M.B.Wilkin, B.H.de Madrid, H.Shimizu, S.Jensen, P.Whiteman, B.Jin, C.Redfield, M.Baron, S.M.Lea, P.A.Handford.
 
  ABSTRACT  
 
The Notch receptor and its ligands are key components in a core metazoan signaling pathway that regulates the spatial patterning, timing and outcome of many cell-fate decisions. Ligands contain a disulfide-rich Delta/Serrate/LAG-2 (DSL) domain required for Notch trans-activation or cis-inhibition. Here we report the X-ray structure of a receptor binding region of a Notch ligand, the DSL-EGF3 domains of human Jagged-1 (J-1(DSL-EGF3)). The structure reveals a highly conserved face of the DSL domain, and we show, by functional analysis of Drosophila melanogster ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with Notch. We also identify, using NMR, a surface of Notch-1 involved in J-1(DSL-EGF3) binding. Our data imply that cis- and trans-regulation may occur through the formation of structurally distinct complexes that, unexpectedly, involve the same surfaces on both ligand and receptor.
 
  Selected figure(s)  
 
Figure 2.
(a) The overall structure of J-1[DSL-EGF3] is shown in a cartoon representation colored from blue at the N terminus (residue 187) to red at the C terminus (residue 335). Disulfide bonds are shown in yellow stick representations, and two views differing by a rotation of 90° about the long axis are shown. (b) Stereo view of the DSL domain fold. (c) Sequences of the four J-1[DSL-EGF3] domains with disulfide bond pairings indicated. (d) Crystallographic structure of N-1[11–13] shown as in a. The bound Ca^2+ in each EGF domain is shown in a space-filling representation. All structural figures were generated with PyMol (http://www.pymol.org/).
Figure 3.
Analysis of an alignment of the Jagged/Delta family DSL domains representing various species (H. sapiens Jagged-1, residues 187–229; D. melanogaster Serrate, residues 237–279; H. sapiens Jagged-2, residues 198–240; H. sapiens Delta-like 1, residues 179–221; D. melanogaster Delta, residues 184–226; H. sapiens Delta-like 4, residues 175–217; C. elegans LAG-2, residues 124–166; H. sapiens Delta-like 3, residues 178–215) (a) and the DSL structure (b) reveals a series of highly conserved, but surface-exposed, residues. Residues that are conserved and predicted to form a Notch binding face are shown in red, cysteines in yellow and a nonconserved residue on the opposite face in blue. (c) Electrostatic surface potential of J-1[DSL-EGF3] and N-1[11–13] plotted at 4 kT e^-1 using APBS^54. Note the positively charged patch (blue) within the DSL domain of Jagged-1 and the negatively charged surface (red) of Notch. The surfaces predicted by sequence/structure analysis (J-1[DSL-EGF3]) and NMR studies (N-1[11–13]) to be involved in binding are highlighted by green bands.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: Nat Struct Biol (2008, 15, 849-857) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21419176 B.Sánchez-Solana, M.L.Nueda, M.D.Ruvira, M.J.Ruiz-Hidalgo, E.M.Monsalve, S.Rivero, J.J.García-Ramírez, M.J.Díaz-Guerra, V.Baladrón, and J.Laborda (2011).
The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities.
  Biochim Biophys Acta, 1813, 1153-1164.  
21215938 D.del Álamo, H.Rouault, and F.Schweisguth (2011).
Mechanism and significance of cis-inhibition in Notch signalling.
  Curr Biol, 21, R40-R47.  
21193018 S.Guo, M.Liu, and R.R.Gonzalez-Perez (2011).
Role of Notch and its oncogenic signaling crosstalk in breast cancer.
  Biochim Biophys Acta, 1815, 197-213.  
20418862 D.Sprinzak, A.Lakhanpal, L.Lebon, L.A.Santat, M.E.Fontes, G.A.Anderson, J.Garcia-Ojalvo, and M.B.Elowitz (2010).
Cis-interactions between Notch and Delta generate mutually exclusive signalling states.
  Nature, 465, 86-90.  
20226663 I.Becam, U.M.Fiuza, A.M.Arias, and M.Milán (2010).
A role of receptor Notch in ligand cis-inhibition in Drosophila.
  Curr Biol, 20, 554-560.  
20486134 I.Dikic, and M.H.Schmidt (2010).
Notch: Implications of endogenous inhibitors for therapy.
  Bioessays, 32, 481-487.  
20192807 J.S.Yuan, P.C.Kousis, S.Suliman, I.Visan, and C.J.Guidos (2010).
Functions of notch signaling in the immune system: consensus and controversies.
  Annu Rev Immunol, 28, 343-365.  
20606624 L.Haklai-Topper, G.Mlechkovich, D.Savariego, I.Gokhman, and A.Yaron (2010).
Cis interaction between Semaphorin6A and Plexin-A4 modulates the repulsive response to Sema6A.
  EMBO J, 29, 2635-2645.  
20437614 R.C.Bauer, A.O.Laney, R.Smith, J.Gerfen, J.J.Morrissette, S.Woyciechowski, J.Garbarini, K.M.Loomes, I.D.Krantz, Z.Urban, B.D.Gelb, E.Goldmuntz, and N.B.Spinner (2010).
Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.
  Hum Mutat, 31, 594-601.  
20590453 R.J.Johnston, and C.Desplan (2010).
Stochastic mechanisms of cell fate specification that yield random or robust outcomes.
  Annu Rev Cell Dev Biol, 26, 689-719.  
20017116 R.L.Rich, and D.G.Myszka (2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
  J Mol Recognit, 23, 1.  
20063416 U.M.Fiuza, T.Klein, A.Martinez Arias, and P.Hayward (2010).
Mechanisms of ligand-mediated inhibition in Notch signaling activity in Drosophila.
  Dev Dyn, 239, 798-805.  
19631544 A.C.Miller, E.L.Lyons, and T.G.Herman (2009).
cis-Inhibition of Notch by endogenous Delta biases the outcome of lateral inhibition.
  Curr Biol, 19, 1378-1383.  
19586525 A.Pintar, C.Guarnaccia, S.Dhir, and S.Pongor (2009).
Exon 6 of human JAG1 encodes a conserved structural unit.
  BMC Struct Biol, 9, 43.
PDB code: 2kb9
19780835 C.Guarnaccia, S.Dhir, A.Pintar, and S.Pongor (2009).
The tetralogy of Fallot-associated G274D mutation impairs folding of the second epidermal growth factor repeat in Jagged-1.
  FEBS J, 276, 6247-6257.  
19417009 C.Opherk, M.Duering, N.Peters, A.Karpinska, S.Rosner, E.Schneider, B.Bader, A.Giese, and M.Dichgans (2009).
CADASIL mutations enhance spontaneous multimerization of NOTCH3.
  Hum Mol Genet, 18, 2761-2767.  
19706274 D.del Alamo, and F.Schweisguth (2009).
Notch signalling: receptor cis-inhibition to achieve directionality.
  Curr Biol, 19, R683-R684.  
18952191 K.B.Luther, and R.S.Haltiwanger (2009).
Role of unusual O-glycans in intercellular signaling.
  Int J Biochem Cell Biol, 41, 1011-1024.  
19379690 R.Kopan, and M.X.Ilagan (2009).
The canonical Notch signaling pathway: unfolding the activation mechanism.
  Cell, 137, 216-233.  
19446531 S.A.Jensen, S.Iqbal, E.D.Lowe, C.Redfield, and P.A.Handford (2009).
Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins.
  Structure, 17, 759-768.
PDB code: 2w86
19608404 S.L.Dunwoodie (2009).
The role of Notch in patterning the human vertebral column.
  Curr Opin Genet Dev, 19, 329-337.  
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 code is shown on the right.