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PDBsum entry 3ksy

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protein links
Signaling protein PDB id
3ksy
Jmol
Contents
Protein chain
1007 a.a. *
* Residue conservation analysis
PDB id:
3ksy
Name: Signaling protein
Title: Crystal structure of the histone domain, dh-ph unit, and catalytic unit of the ras activator son of sevenless (sos)
Structure: Son of sevenless homolog 1. Chain: a. Fragment: sos-hdpc, (unp residues 1-1049). Synonym: sos-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sos1. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
3.18Å     R-factor:   0.264     R-free:   0.312
Authors: J.Gureasko,O.Kuchment,J.Kuriyan
Key ref:
J.Gureasko et al. (2010). Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. Proc Natl Acad Sci U S A, 107, 3430-3435. PubMed id: 20133692 DOI: 10.1073/pnas.0913915107
Date:
24-Nov-09     Release date:   16-Feb-10    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q07889  (SOS1_HUMAN) -  Son of sevenless homolog 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1333 a.a.
1007 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     small GTPase mediated signal transduction   3 terms 
  Biochemical function     DNA binding     4 terms  

 

 
DOI no: 10.1073/pnas.0913915107 Proc Natl Acad Sci U S A 107:3430-3435 (2010)
PubMed id: 20133692  
 
 
Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless.
J.Gureasko, O.Kuchment, D.L.Makino, H.Sondermann, D.Bar-Sagi, J.Kuriyan.
 
  ABSTRACT  
 
Membrane-bound Ras is activated by translocation of the Son of Sevenless (SOS) protein to the plasma membrane. SOS is inactive unless Ras is bound to an allosteric site on SOS, and the Dbl homology (DH) and Pleckstrin homology (PH) domains of SOS (the DH-PH unit) block allosteric Ras binding. We showed previously that the activity of SOS at the membrane increases with the density of PIP(2) and the local concentration of Ras-GTP, which synergize to release the DH-PH unit. Here we present a new crystal structure of SOS that contains the N-terminal histone domain in addition to the DH-PH unit and the catalytic unit (SOS(HDFC), residues 1-1049). The structure reveals that the histone domain plays a dual role in occluding the allosteric site and in stabilizing the autoinhibitory conformation of the DH-PH unit. Additional insight is provided by kinetic analysis of the activation of membrane-bound Ras by mutant forms of SOS that contain mutations in the histone and the PH domains (E108K, C441Y, and E433K) that are associated with Noonan syndrome, a disease caused by hyperactive Ras signaling. Our results indicate that the histone domain and the DH-PH unit are conformationally coupled, and that the simultaneous engagement of the membrane by a PH domain PIP(2)-binding interaction and electrostatic interactions between a conserved positively charged patch on the histone domain and the negatively charged membrane coincides with a productive reorientation of SOS at the membrane and increased accessibility of both Ras binding sites on SOS.
 
  Selected figure(s)  
 
Figure 1.
Structure of SOS^HDPC. (A) Domain organization of SOS, with the Noonan syndrome-associated mutations that map to the histone domain, the PH domain and the PH-Rem linker indicated. (B) Crystal structure of SOS^HDPC, with coloring according to the diagram in (A).
Figure 2.
Allosteric Ras binding site is occluded by the histone and the DH domains. (A) The structure of autoinhibited SOS^HDPC is shown at the membrane. To model Ras at both the active and allosteric Ras binding sites, the structures of SOS^HDPC and the ternary Ras∶SOS^cat∶Ras-GTP complex (3) were aligned through superpositioning of the two respective Rem domains of SOS^HDPC and SOS^cat. Note that the Ras-GTP bound at the allosteric site in the ternary complex overlaps with the histone and the DH domains of SOS^HDPC. (B) Close up view of the occlusion of the allosteric site by the histone domain. Only the histone domain from SOS^HDPC and the Ras-GTP from the ternary complex are shown for clarity.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21404360 C.G.Kalodimos (2011).
NMR reveals novel mechanisms of protein activity regulation.
  Protein Sci, 20, 773-782.  
20495561 J.T.Groves, and J.Kuriyan (2010).
Molecular mechanisms in signal transduction at the membrane.
  Nat Struct Mol Biol, 17, 659-665.  
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.