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PDBsum entry 1far

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Serine/threonine protein kinase PDB id
1far
Jmol
Contents
Protein chain
52 a.a. *
Metals
_ZN ×2
* Residue conservation analysis
PDB id:
1far
Name: Serine/threonine protein kinase
Title: Raf-1 cysteine rich domain, nmr, minimized average structure
Structure: Raf-1. Chain: a. Fragment: cysteine-rich domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 1 models
Authors: H.R.Mott,S.L.Campbell
Key ref: H.R.Mott et al. (1996). The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site. Proc Natl Acad Sci U S A, 93, 8312-8317. PubMed id: 8710867
Date:
05-Sep-96     Release date:   27-Jan-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04049  (RAF1_HUMAN) -  RAF proto-oncogene serine/threonine-protein kinase
Seq:
Struc:
 
Seq:
Struc:
648 a.a.
52 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     intracellular signal transduction   1 term 

 

 
    reference    
 
 
Proc Natl Acad Sci U S A 93:8312-8317 (1996)
PubMed id: 8710867  
 
 
The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site.
H.R.Mott, J.W.Carpenter, S.Zhong, S.Ghosh, R.M.Bell, S.L.Campbell.
 
  ABSTRACT  
 
The Raf-1 protein kinase is the best-characterized downstream effector of activated Ras. Interaction with Ras leads to Raf-1 activation and results in transduction of cell growth and differentiation signals. The details of Raf-1 activation are unclear, but our characterization of a second Ras-binding site in the cysteine-rich domain (CRD) and the involvement of both Ras-binding sites in effective Raf-1-mediated transformation provides insight into the molecular aspects and consequences of Ras-Raf interactions. The Raf-1 CRD is a member of an emerging family of domains, many of which are found within signal transducing proteins. Several contain binding sites for diacylglycerol (or phorbol esters) and phosphatidylserine and are believed to play a role in membrane translocation and enzyme activation. The CRD from Raf-1 does not bind diacylglycerol but interacts with Ras and phosphatidylserine. To investigate the ligand-binding specificities associated with CRDs, we have determined the solution structure of the Raf-1 CRD using heteronuclear multidimensional NMR. We show that there are differences between this structure and the structures of two related domains from protein kinase C (PKC). The differences are confined to regions of the CRDs involved in binding phorbol ester in the PKC domains. Since phosphatidylserine is a common ligand, we expect its binding site to be located in regions where the structures of the Raf-1 and PKC domains are similar. The structure of the Raf-1 CRD represents an example of this family of domains that does not bind diacylglycerol and provides a framework for investigating its interactions with other molecules.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21419781 M.D.Stewart, B.Morgan, F.Massi, and T.I.Igumenova (2011).
Probing the determinants of diacylglycerol binding affinity in the C1B domain of protein kinase Cα.
  J Mol Biol, 408, 949-970.  
19668861 M.D.Smith, C.G.Sudhahar, D.Gong, R.V.Stahelin, and M.D.Best (2009).
Modular synthesis of biologically active phosphatidic acid probes using click chemistry.
  Mol Biosyst, 5, 962-972.  
19948477 T.Niault, I.Sobczak, K.Meissl, G.Weitsman, D.Piazzolla, G.Maurer, F.Kern, K.Ehrenreiter, M.Hamerl, I.Moarefi, T.Leung, O.Carugo, T.Ng, and M.Baccarini (2009).
From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-alpha kinase activity.
  J Cell Biol, 187, 335-342.  
18589439 J.E.Chrencik, A.Brooun, H.Zhang, I.I.Mathews, G.L.Hura, S.A.Foster, J.J.Perry, M.Streiff, P.Ramage, H.Widmer, G.M.Bokoch, J.A.Tainer, G.Weckbecker, and P.Kuhn (2008).
Structural basis of guanine nucleotide exchange mediated by the T-cell essential Vav1.
  J Mol Biol, 380, 828-843.
PDB code: 3bji
18511940 J.Rapley, V.L.Tybulewicz, and K.Rittinger (2008).
Crucial structural role for the PH and C1 domains of the Vav1 exchange factor.
  EMBO Rep, 9, 655-661.
PDB code: 2vrw
17496912 A.Clapéron, and M.Therrien (2007).
KSR and CNK: two scaffolds regulating RAS-mediated RAF activation.
  Oncogene, 26, 3143-3158.  
17555829 D.T.Leicht, V.Balan, A.Kaplun, V.Singh-Gupta, L.Kaplun, M.Dobson, and G.Tzivion (2007).
Raf kinases: function, regulation and role in human cancer.
  Biochim Biophys Acta, 1773, 1196-1212.  
17500509 H.Al-Ali, T.J.Ragan, X.Gao, and T.K.Harris (2007).
Reconstitution of modular PDK1 functions on trans-splicing of the regulatory PH and catalytic kinase domains.
  Bioconjug Chem, 18, 1294-1302.  
18020980 V.Khazak, I.Astsaturov, I.G.Serebriiskii, and E.A.Golemis (2007).
Selective Raf inhibition in cancer therapy.
  Expert Opin Ther Targets, 11, 1587-1609.  
16698549 E.Harjes, S.Harjes, S.Wohlgemuth, K.H.Müller, E.Krieger, C.Herrmann, and P.Bayer (2006).
GTP-Ras disrupts the intramolecular complex of C1 and RA domains of Nore1.
  Structure, 14, 881-888.
PDB code: 2fnf
16858395 K.Terai, and M.Matsuda (2006).
The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf.
  EMBO J, 25, 3556-3564.  
  19641676 I.Korichneva (2005).
Redox regulation of cardiac protein kinase C.
  Exp Clin Cardiol, 10, 256-261.  
12814644 B.R.Lentz (2003).
Exposure of platelet membrane phosphatidylserine regulates blood coagulation.
  Prog Lipid Res, 42, 423-438.  
11933072 E.Y.Chan, S.L.Stang, D.A.Bottorff, and J.C.Stone (2002).
Mutations in conserved regions 1, 2, and 3 of Raf-1 that activate transforming activity.
  Mol Carcinog, 33, 189-197.  
11909943 M.A.Booden, S.L.Campbell, and C.J.Der (2002).
Critical but distinct roles for the pleckstrin homology and cysteine-rich domains as positive modulators of Vav2 signaling and transformation.
  Mol Cell Biol, 22, 2487-2497.  
12191592 M.Rizzo, and G.Romero (2002).
Pharmacological importance of phospholipase D and phosphatidic acid in the regulation of the mitogen-activated protein kinase cascade.
  Pharmacol Ther, 94, 35-50.  
12134072 T.Bondeva, A.Balla, P.Várnai, and T.Balla (2002).
Structural determinants of Ras-Raf interaction analyzed in live cells.
  Mol Biol Cell, 13, 2323-2333.  
11259591 A.Chiloeches, C.S.Mason, and R.Marais (2001).
S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3.
  Mol Cell Biol, 21, 2423-2434.  
11384750 E.Kerkhoff, and U.R.Rapp (2001).
The Ras-Raf relationship: an unfinished puzzle.
  Adv Enzyme Regul, 41, 261-267.  
11292843 N.V.Grishin (2001).
Treble clef finger--a functionally diverse zinc-binding structural motif.
  Nucleic Acids Res, 29, 1703-1714.  
10848612 A.Yuryev, M.Ono, S.A.Goff, F.Macaluso, and L.P.Wennogle (2000).
Isoform-specific localization of A-RAF in mitochondria.
  Mol Cell Biol, 20, 4870-4878.  
11032810 B.H.Zhang, and K.L.Guan (2000).
Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601.
  EMBO J, 19, 5429-5439.  
10993914 B.Hoyos, A.Imam, R.Chua, C.Swenson, G.X.Tong, E.Levi, N.Noy, and U.Hämmerling (2000).
The cysteine-rich regions of the regulatory domains of Raf and protein kinase C as retinoid receptors.
  J Exp Med, 192, 835-845.  
11337027 C.R.Weinstein-Oppenheimer, W.L.Blalock, L.S.Steelman, F.Chang, and J.A.McCubrey (2000).
The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors.
  Pharmacol Ther, 88, 229-279.  
10940243 J.H.Hurley, and S.Misra (2000).
Signaling and subcellular targeting by membrane-binding domains.
  Annu Rev Biophys Biomol Struct, 29, 49-79.  
10025402 C.Ostermeier, and A.T.Brunger (1999).
Structural basis of Rab effector specificity: crystal structure of the small G protein Rab3A complexed with the effector domain of rabphilin-3A.
  Cell, 96, 363-374.
PDB code: 1zbd
10205168 C.S.Mason, C.J.Springer, R.G.Cooper, G.Superti-Furga, C.J.Marshall, and R.Marais (1999).
Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation.
  EMBO J, 18, 2137-2148.  
  10490616 D.J.Bartels, D.A.Mitchell, X.Dong, and R.J.Deschenes (1999).
Erf2, a novel gene product that affects the localization and palmitoylation of Ras2 in Saccharomyces cerevisiae.
  Mol Cell Biol, 19, 6775-6787.  
  10454553 T.Okada, C.D.Hu, T.G.Jin, K.Kariya, Y.Yamawaki-Kataoka, and T.Kataoka (1999).
The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family small GTPases.
  Mol Cell Biol, 19, 6057-6064.  
9450998 G.Müller, P.Storz, S.Bourteele, H.Döppler, K.Pfizenmaier, H.Mischak, A.Philipp, C.Kaiser, and W.Kolch (1998).
Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling.
  EMBO J, 17, 732-742.  
  9774683 M.Daub, J.Jöckel, T.Quack, C.K.Weber, F.Schmitz, U.R.Rapp, A.Wittinghofer, and C.Block (1998).
The RafC1 cysteine-rich domain contains multiple distinct regulatory epitopes which control Ras-dependent Raf activation.
  Mol Cell Biol, 18, 6698-6710.  
9689060 R.E.Cutler, R.M.Stephens, M.R.Saracino, and D.K.Morrison (1998).
Autoregulation of the Raf-1 serine/threonine kinase.
  Proc Natl Acad Sci U S A, 95, 9214-9219.  
9069266 A.C.Newton (1997).
Regulation of protein kinase C.
  Curr Opin Cell Biol, 9, 161-167.  
9069260 D.K.Morrison, and R.E.Cutler (1997).
The complexity of Raf-1 regulation.
  Curr Opin Cell Biol, 9, 174-179.  
  9041654 J.H.Hurley, A.C.Newton, P.J.Parker, P.M.Blumberg, and Y.Nishizuka (1997).
Taxonomy and function of C1 protein kinase C homology domains.
  Protein Sci, 6, 477-480.  
9266179 J.H.Hurley, and J.A.Grobler (1997).
Protein kinase C and phospholipase C: bilayer interactions and regulation.
  Curr Opin Struct Biol, 7, 557-565.  
  9284129 J.R.Daugherty, C.I.Murphy, L.A.Doros-Richert, A.Barbosa, L.O.Kashala, W.R.Ballou, N.J.Snellings, C.F.Ockenhouse, and D.E.Lanar (1997).
Baculovirus-mediated expression of Plasmodium falciparum erythrocyte binding antigen 175 polypeptides and their recognition by human antibodies.
  Infect Immun, 65, 3631-3637.  
9434896 M.Geyer, and A.Wittinghofer (1997).
GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins.
  Curr Opin Struct Biol, 7, 786-792.  
9371754 N.R.Michaud, M.Therrien, A.Cacace, L.C.Edsall, S.Spiegel, G.M.Rubin, and D.K.Morrison (1997).
KSR stimulates Raf-1 activity in a kinase-independent manner.
  Proc Natl Acad Sci U S A, 94, 12792-12796.  
9155021 R.E.Cutler, and D.K.Morrison (1997).
Mammalian Raf-1 is activated by mutations that restore Raf signaling in Drosophila.
  EMBO J, 16, 1953-1960.  
9230043 Y.Ito, K.Yamasaki, J.Iwahara, T.Terada, A.Kamiya, M.Shirouzu, Y.Muto, G.Kawai, S.Yokoyama, E.D.Laue, M.Wälchli, T.Shibata, S.Nishimura, and T.Miyazawa (1997).
Regional polysterism in the GTP-bound form of the human c-Ha-Ras protein.
  Biochemistry, 36, 9109-9119.
PDB code: 1aa9
  8972184 Z.Luo, B.Diaz, M.S.Marshall, and J.Avruch (1997).
An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ.
  Mol Cell Biol, 17, 46-53.  
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.