PDBsum entry 1xd2

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protein ligands metals Protein-protein interface(s) links
Signaling protein PDB id
Protein chains
166 a.a. *
469 a.a. *
PO4 ×4
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of a ternary ras:sos:ras Gdp complex
Structure: Transforming protein p21/h-ras-1. Chain: a. Fragment: residues 1-166. Synonym: c-h-ras. Engineered: yes. Mutation: yes. Transforming protein p21/h-ras-1. Chain: b. Fragment: residues 1-166.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hras, hras1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: sos1.
Biol. unit: Trimer (from PQS)
2.70Å     R-factor:   0.212     R-free:   0.245
Authors: H.Sondermann,S.M.Soisson,S.Boykevisch,S.S.Yang,D.Bar-Sagi, J.Kuriyan
Key ref:
H.Sondermann et al. (2004). Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell, 119, 393-405. PubMed id: 15507210 DOI: 10.1016/j.cell.2004.10.005
03-Sep-04     Release date:   02-Nov-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P01112  (RASH_HUMAN) -  GTPase HRas
189 a.a.
166 a.a.*
Protein chain
Pfam   ArchSchema ?
Q07889  (SOS1_HUMAN) -  Son of sevenless homolog 1
1333 a.a.
469 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!
  Cellular component     intracellular   2 terms 
  Biological process     signal transduction   5 terms 
  Biochemical function     guanyl-nucleotide exchange factor activity     2 terms  


DOI no: 10.1016/j.cell.2004.10.005 Cell 119:393-405 (2004)
PubMed id: 15507210  
Structural analysis of autoinhibition in the Ras activator Son of sevenless.
H.Sondermann, S.M.Soisson, S.Boykevisch, S.S.Yang, D.Bar-Sagi, J.Kuriyan.
The classical model for the activation of the nucleotide exchange factor Son of sevenless (SOS) involves its recruitment to the membrane, where it engages Ras. The recent discovery that Ras*GTP is an allosteric activator of SOS indicated that the regulation of SOS is more complex than originally envisaged. We now present crystallographic and biochemical analyses of a construct of SOS that contains the Dbl homology-pleckstrin homology (DH-PH) and catalytic domains and show that the DH-PH unit blocks the allosteric binding site for Ras and suppresses the activity of SOS. SOS is dependent on Ras binding to the allosteric site for both a lower level of activity, which is a result of Ras*GDP binding, and maximal activity, which requires Ras*GTP. The action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, in which Ras converts SOS from low to high activity forms as Ras*GDP is converted to Ras*GTP by SOS.
  Selected figure(s)  
Figure 1.
Figure 1. Structure of SOS^DH-PH-cat(A) Domain organization of SOS and overview of a ternary Ras:SOS complex. The crystal structure of the Ras:SOS^cat:Ras^Y64A•GppNp ternary complex is shown (Margarit et al., 2003; PDB code 1NVV). The helical hairpin of the Cdc25 domain is shown in orange.(B) The crystal structure of SOS^DH-PH-cat. Two orthogonal views are shown with coloring according to the diagram shown in (A).(C) Comparison of SOS^DH-PH-cat with the structure of the ternary Ras:SOS^cat:Ras•GTP complex (PDB code 1NVV). The structures were aligned through superpositioning of the two respective Rem domains of SOS^DH-PH-cat and SOS^cat. Ras at the catalytic site is not shown for clarity (see [A]). Note that the distal Ras^Y64A•GppNp (green) in the ternary complex overlaps with the DH domain of SOS^DH-PH-cat. A close-up view of the Rem-Cdc25 interface is shown (right).
Figure 6.
Figure 6. Activation of ERK MAP Kinase by SOSCOS1 cells were transiently cotransfected with HA-tagged ERK2 and T7-tagged SOS constructs as indicated. ERK2 activation was measured in serum-starved cells by an immunoprecipitated kinase-kinase assay using myelin basic protein (MBP) as a substrate. Results were normalized to the vector control reaction. Western blots detecting T7- and HA-tagged proteins are shown. (A) Activation of ERK2 by SOS^cat and SOS^cat mutants. Results shown in the bar diagram are from three independent experiments. Error bars indicate standard deviations of three independent experiments. The amout of ^32P incorporation into MBP was quantified by phosphorimaging. Autoradiograms and Western blots shown are from a single representative experiment. (B) Activation of ERK2 by SOS truncations. Results shown are from a single representative experiment. Experiments were repeated three times with similar results.
  The above figures are reprinted by permission from Cell Press: Cell (2004, 119, 393-405) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23178454 R.Baker, S.M.Lewis, A.T.Sasaki, E.M.Wilkerson, J.W.Locasale, L.C.Cantley, B.Kuhlman, H.G.Dohlman, and S.L.Campbell (2013).
Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function.
  Nat Struct Mol Biol, 20, 46-52.  
21111786 A.Fernández-Medarde, and E.Santos (2011).
The RasGrf family of mammalian guanine nucleotide exchange factors.
  Biochim Biophys Acta, 1815, 170-188.  
20949621 L.Gremer, T.Merbitz-Zahradnik, R.Dvorsky, I.C.Cirstea, C.P.Kratz, M.Zenker, A.Wittinghofer, and M.R.Ahmadian (2011).
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.
  Hum Mutat, 32, 33-43.  
22081014 P.D.Mace, Y.Wallez, M.K.Dobaczewska, J.J.Lee, H.Robinson, E.B.Pasquale, and S.J.Riedl (2011).
NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling.
  Nat Struct Mol Biol, 18, 1381-1387.
PDB codes: 3t6a 3t6g
20367082 A.K.Chakraborty, and A.Kosmrlj (2010).
Statistical mechanical concepts in immunology.
  Annu Rev Phys Chem, 61, 283-303.  
20029448 A.K.Chakraborty, and J.Das (2010).
Pairing computation with experimentation: a powerful coupling for understanding T cell signalling.
  Nat Rev Immunol, 10, 59-71.  
20141838 B.Yu, I.R.Martins, P.Li, G.K.Amarasinghe, J.Umetani, M.E.Fernandez-Zapico, D.D.Billadeau, M.Machius, D.R.Tomchick, and M.K.Rosen (2010).
Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1.
  Cell, 140, 246-256.
PDB code: 3ky9
20924370 J.B.Bruning, A.A.Parent, G.Gil, M.Zhao, J.Nowak, M.C.Pace, C.L.Smith, P.V.Afonine, P.D.Adams, J.A.Katzenellenbogen, and K.W.Nettles (2010).
Coupling of receptor conformation and ligand orientation determine graded activity.
  Nat Chem Biol, 6, 837-843.
PDB codes: 2qxs 2qzo 3os8 3os9 3osa
20133692 J.Gureasko, O.Kuchment, D.L.Makino, H.Sondermann, D.Bar-Sagi, and J.Kuriyan (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.
PDB code: 3ksy
20495561 J.T.Groves, and J.Kuriyan (2010).
Molecular mechanisms in signal transduction at the membrane.
  Nat Struct Mol Biol, 17, 659-665.  
20585582 K.F.Ahmad, and W.A.Lim (2010).
The minimal autoinhibited unit of the guanine nucleotide exchange factor intersectin.
  PLoS One, 5, e11291.
PDB code: 3jv3
20461756 M.C.Jongmans, P.M.Hoogerbrugge, L.Hilkens, U.Flucke, I.van der Burgt, K.Noordam, M.Ruiterkamp-Versteeg, H.G.Yntema, W.M.Nillesen, M.J.Ligtenberg, A.G.van Kessel, R.P.Kuiper, and N.Hoogerbrugge (2010).
Noonan syndrome, the SOS1 gene and embryonal rhabdomyosarcoma.
  Genes Chromosomes Cancer, 49, 635-641.  
20018863 M.T.Mazhab-Jafari, C.B.Marshall, M.Smith, G.M.Gasmi-Seabrook, V.Stambolic, R.Rottapel, B.G.Neel, and M.Ikura (2010).
Real-time NMR study of three small GTPases reveals that fluorescent 2'(3')-O-(N-methylanthraniloyl)-tagged nucleotides alter hydrolysis and exchange kinetics.
  J Biol Chem, 285, 5132-5136.  
20958325 M.Tartaglia, and B.D.Gelb (2010).
Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.
  Ann N Y Acad Sci, 1214, 99.  
  20648242 M.Tartaglia, G.Zampino, and B.D.Gelb (2010).
Noonan syndrome: clinical aspects and molecular pathogenesis.
  Mol Syndromol, 1, 2.  
19366993 A.K.Chakraborty, J.Das, J.Zikherman, M.Yang, C.C.Govern, M.Ho, A.Weiss, and J.Roose (2009).
Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes.
  Sci Signal, 2, pt2.  
19098101 A.Prasad, J.Zikherman, J.Das, J.P.Roose, A.Weiss, and A.K.Chakraborty (2009).
Origin of the sharp boundary that discriminates positive and negative selection of thymocytes.
  Proc Natl Acad Sci U S A, 106, 528-533.  
19323566 C.B.McDonald, K.L.Seldeen, B.J.Deegan, and A.Farooq (2009).
SH3 domains of Grb2 adaptor bind to PXpsiPXR motifs within the Sos1 nucleotide exchange factor in a discriminate manner.
  Biochemistry, 48, 4074-4085.  
19002579 E.Zhuravliova, T.Barbakadze, N.Narmania, M.Sepashvili, and D.G.Mikeladze (2009).
Hypoinsulinemia alleviates the GRF1/Ras/Akt anti-apoptotic pathway and induces alterations of mitochondrial ras trafficking in neuronal cells.
  Neurochem Res, 34, 1076-1082.  
19167334 J.Das, M.Ho, J.Zikherman, C.Govern, M.Yang, A.Weiss, A.K.Chakraborty, and J.P.Roose (2009).
Digital signaling and hysteresis characterize ras activation in lymphoid cells.
  Cell, 136, 337-351.  
19566183 J.Das, M.Kardar, and A.K.Chakraborty (2009).
Positive feedback regulation results in spatial clustering and fast spreading of active signaling molecules on a cell membrane.
  J Chem Phys, 130, 245102.  
19141281 T.S.Freedman, H.Sondermann, O.Kuchment, G.D.Friedland, T.Kortemme, and J.Kuriyan (2009).
Differences in flexibility underlie functional differences in the Ras activators son of sevenless and Ras guanine nucleotide releasing factor 1.
  Structure, 17, 41-53.  
  18212529 A.Harding, and J.F.Hancock (2008).
Ras nanoclusters: combining digital and analog signaling.
  Cell Cycle, 7, 127-134.  
18025104 C.Sampaio, M.Dance, A.Montagner, T.Edouard, N.Malet, B.Perret, A.Yart, J.P.Salles, and P.Raynal (2008).
Signal strength dictates phosphoinositide 3-kinase contribution to Ras/extracellular signal-regulated kinase 1 and 2 activation via differential Gab1/Shp2 recruitment: consequences for resistance to epidermal growth factor receptor inhibition.
  Mol Cell Biol, 28, 587-600.  
18523461 G.M.Findlay, and T.Pawson (2008).
How is SOS activated? Let us count the ways.
  Nat Struct Mol Biol, 15, 538-540.  
18454158 J.Gureasko, W.J.Galush, S.Boykevisch, H.Sondermann, D.Bar-Sagi, J.T.Groves, and J.Kuriyan (2008).
Membrane-dependent signal integration by the Ras activator Son of sevenless.
  Nat Struct Mol Biol, 15, 452-461.  
18064648 K.D.Swanson, J.M.Winter, M.Reis, M.Bentires-Alj, H.Greulich, R.Grewal, R.H.Hruban, C.J.Yeo, Y.Yassin, O.Iartchouk, K.Montgomery, S.P.Whitman, M.A.Caligiuri, M.L.Loh, D.G.Gilliland, A.T.Look, R.Kucherlapati, S.E.Kern, M.Meyerson, and B.G.Neel (2008).
SOS1 mutations are rare in human malignancies: Implications for Noonan syndrome patients.
  Genes Chromosomes Cancer, 47, 253-259.  
19026786 K.D.Swanson, Y.Tang, D.F.Ceccarelli, F.Poy, J.P.Sliwa, B.G.Neel, and M.J.Eck (2008).
The Skap-hom dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch.
  Mol Cell, 32, 564-575.
PDB codes: 1u5g 2otx
18541156 L.Buday, and J.Downward (2008).
Many faces of Ras activation.
  Biochim Biophys Acta, 1786, 178-187.  
18972187 R.Tanizaki, A.Katsumi, H.Kiyoi, S.Kunishima, T.Iwasaki, Y.Ishikawa, M.Kobayashi, A.Abe, T.Matsushita, T.Watanabe, T.Kojima, K.Kaibuchi, S.Kojima, and T.Naoe (2008).
Mutational analysis of SOS1 gene in acute myeloid leukemia.
  Int J Hematol, 88, 460-462.  
18651097 Y.Narumi, Y.Aoki, T.Niihori, M.Sakurai, H.Cavé, A.Verloes, K.Nishio, H.Ohashi, K.Kurosawa, N.Okamoto, H.Kawame, S.Mizuno, T.Kondoh, M.C.Addor, A.Coeslier-Dieux, C.Vincent-Delorme, K.Tabayashi, M.Aoki, T.Kobayashi, A.Guliyeva, S.Kure, and Y.Matsubara (2008).
Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome.
  J Hum Genet, 53, 834-841.  
17450153 A.Delprato, and D.G.Lambright (2007).
Structural basis for Rab GTPase activation by VPS9 domain exchange factors.
  Nat Struct Mol Biol, 14, 406-412.
PDB code: 2ot3
17143285 A.E.Roberts, T.Araki, K.D.Swanson, K.T.Montgomery, T.A.Schiripo, V.A.Joshi, L.Li, Y.Yassin, A.M.Tamburino, B.G.Neel, and R.S.Kucherlapati (2007).
Germline gain-of-function mutations in SOS1 cause Noonan syndrome.
  Nat Genet, 39, 70-74.  
17540168 J.L.Bos, H.Rehmann, and A.Wittinghofer (2007).
GEFs and GAPs: critical elements in the control of small G proteins.
  Cell, 129, 865-877.  
18042453 J.P.DiNitto, A.Delprato, M.T.Gabe Lee, T.C.Cronin, S.Huang, A.Guilherme, M.P.Czech, and D.G.Lambright (2007).
Structural basis and mechanism of autoregulation in 3-phosphoinositide-dependent Grp1 family Arf GTPase exchange factors.
  Mol Cell, 28, 569-583.
PDB codes: 2r09 2r0d
17283063 J.P.Roose, M.Mollenauer, M.Ho, T.Kurosaki, and A.Weiss (2007).
Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes.
  Mol Cell Biol, 27, 2732-2745.  
17339331 K.Modzelewska, M.G.Elgort, J.Huang, G.Jongeward, A.Lauritzen, C.H.Yoon, P.W.Sternberg, and N.Moghal (2007).
An activating mutation in sos-1 identifies its Dbl domain as a critical inhibitor of the epidermal growth factor receptor pathway during Caenorhabditis elegans vulval development.
  Mol Cell Biol, 27, 3695-3707.  
17391702 M.K.Chhatriwala, L.Betts, D.K.Worthylake, and J.Sondek (2007).
The DH and PH domains of Trio coordinately engage Rho GTPases for their efficient activation.
  J Mol Biol, 368, 1307-1320.
PDB code: 2nz8
17496910 M.M.McKay, and D.K.Morrison (2007).
Integrating signals from RTKs to ERK/MAPK.
  Oncogene, 26, 3113-3121.  
17143282 M.Tartaglia, L.A.Pennacchio, C.Zhao, K.K.Yadav, V.Fodale, A.Sarkozy, B.Pandit, K.Oishi, S.Martinelli, W.Schackwitz, A.Ustaszewska, J.Martin, J.Bristow, C.Carta, F.Lepri, C.Neri, I.Vasta, K.Gibson, C.J.Curry, J.P.Siguero, M.C.Digilio, G.Zampino, B.Dallapiccola, D.Bar-Sagi, and B.D.Gelb (2007).
Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.
  Nat Genet, 39, 75-79.  
17586837 M.Zenker, D.Horn, D.Wieczorek, J.Allanson, S.Pauli, I.van der Burgt, H.G.Doerr, H.Gaspar, M.Hofbeck, G.Gillessen-Kaesbach, A.Koch, P.Meinecke, S.Mundlos, A.Nowka, A.Rauch, S.Reif, C.von Schnakenburg, H.Seidel, L.E.Wehner, C.Zweier, S.Bauhuber, V.Matejas, C.P.Kratz, C.Thomas, and K.Kutsche (2007).
SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome.
  J Med Genet, 44, 651-656.  
17384584 S.Schubbert, K.Shannon, and G.Bollag (2007).
Hyperactive Ras in developmental disorders and cancer.
  Nat Rev Cancer, 7, 295-308.  
16356724 A.Wittinghofer (2006).
Phosphoryl transfer in Ras proteins, conclusive or elusive?
  Trends Biochem Sci, 31, 20-23.  
16531227 B.Ford, V.Hornak, H.Kleinman, and N.Nassar (2006).
Structure of a transient intermediate for GTP hydrolysis by ras.
  Structure, 14, 427-436.
PDB codes: 1zvq 1zw6
16906159 J.C.Houtman, H.Yamaguchi, M.Barda-Saad, A.Braiman, B.Bowden, E.Appella, P.Schuck, and L.E.Samelson (2006).
Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1.
  Nat Struct Mol Biol, 13, 798-805.  
17084704 S.Boykevisch, C.Zhao, H.Sondermann, P.Philippidou, S.Halegoua, J.Kuriyan, and D.Bar-Sagi (2006).
Regulation of ras signaling dynamics by Sos-mediated positive feedback.
  Curr Biol, 16, 2173-2179.  
17075039 T.S.Freedman, H.Sondermann, G.D.Friedland, T.Kortemme, D.Bar-Sagi, S.Marqusee, and J.Kuriyan (2006).
A Ras-induced conformational switch in the Ras activator Son of sevenless.
  Proc Natl Acad Sci U S A, 103, 16692-16697.
PDB codes: 2ii0 2ije
15886107 A.Harding, T.Tian, E.Westbury, E.Frische, and J.F.Hancock (2005).
Subcellular localization determines MAP kinase signal output.
  Curr Biol, 15, 869-873.  
16139957 B.B.Friday, and A.A.Adjei (2005).
K-ras as a target for cancer therapy.
  Biochim Biophys Acta, 1756, 127-144.  
16267129 H.Sondermann, B.Nagar, D.Bar-Sagi, and J.Kuriyan (2005).
Computational docking and solution x-ray scattering predict a membrane-interacting role for the histone domain of the Ras activator son of sevenless.
  Proc Natl Acad Sci U S A, 102, 16632-16637.  
15688002 K.L.Rossman, C.J.Der, and J.Sondek (2005).
GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors.
  Nat Rev Mol Cell Biol, 6, 167-180.  
15817389 K.L.Rossman, and J.Sondek (2005).
Larger than Dbl: new structural insights into RhoA activation.
  Trends Biochem Sci, 30, 163-165.  
16051167 N.Mitin, K.L.Rossman, and C.J.Der (2005).
Signaling interplay in Ras superfamily function.
  Curr Biol, 15, R563-R574.  
15837192 S.Pasqualato, and J.Cherfils (2005).
Crystallographic evidence for substrate-assisted GTP hydrolysis by a small GTP binding protein.
  Structure, 13, 533-540.
PDB code: 1oix
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