3omv | pdb_00003omv

Crystal structure of c-raf (raf-1)

Structural highlights

3omv is a 2 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 3lb7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	SM5
Related:	3d4q
Gene:	RAF1, RAF (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[RAF1_HUMAN] Defects in RAF1 are the cause of Noonan syndrome type 5 (NS5) [MIM:611553]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births.^[1] ^[2] ^[3] Defects in RAF1 are the cause of LEOPARD syndrome type 2 (LEOPARD2) [MIM:611554]. LEOPARD syndrome is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness.^[4]

Function

[RAF1_HUMAN] Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.,Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S Nature. 2010 Mar 18;464(7287):431-5. Epub 2010 Feb 3. PMID:20130576^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1. PMID:17603483 doi:10.1038/ng2073
↑ Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7. Epub 2007 Jul 1. PMID:17603482 doi:ng2078
↑ Longoni M, Moncini S, Cisternino M, Morella IM, Ferraiuolo S, Russo S, Mannarino S, Brazzelli V, Coi P, Zippel R, Venturin M, Riva P. Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations. Am J Med Genet A. 2010 Sep;152A(9):2176-84. doi: 10.1002/ajmg.a.33564. PMID:20683980 doi:10.1002/ajmg.a.33564
↑ Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1. PMID:17603483 doi:10.1038/ng2073
↑ Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, Morrice N, Moelling K, Aitken A. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem. 1997 Nov 14;272(46):28882-8. PMID:9360956
↑ Chen J, Fujii K, Zhang L, Roberts T, Fu H. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7783-8. Epub 2001 Jun 26. PMID:11427728 doi:10.1073/pnas.141224398
↑ Broustas CG, Grammatikakis N, Eto M, Dent P, Brautigan DL, Kasid U. Phosphorylation of the myosin-binding subunit of myosin phosphatase by Raf-1 and inhibition of phosphatase activity. J Biol Chem. 2002 Jan 25;277(4):3053-9. Epub 2001 Nov 21. PMID:11719507 doi:10.1074/jbc.M106343200
↑ Ding Q, Gros R, Gray ID, Taussig R, Ferguson SS, Feldman RD. Raf kinase activation of adenylyl cyclases: isoform-selective regulation. Mol Pharmacol. 2004 Oct;66(4):921-8. PMID:15385642 doi:10.1124/mol.66.4.
↑ O'Neill E, Rushworth L, Baccarini M, Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science. 2004 Dec 24;306(5705):2267-70. PMID:15618521 doi:10.1126/science.1103233
↑ Jin S, Zhuo Y, Guo W, Field J. p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. J Biol Chem. 2005 Jul 1;280(26):24698-705. Epub 2005 Apr 22. PMID:15849194 doi:10.1074/jbc.M413374200
↑ Wang Z, Wade P, Mandell KJ, Akyildiz A, Parkos CA, Mrsny RJ, Nusrat A. Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription factor slug. Oncogene. 2007 Feb 22;26(8):1222-30. Epub 2006 Aug 21. PMID:16924233 doi:10.1038/sj.onc.1209902
↑ Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010 Mar 18;464(7287):431-5. Epub 2010 Feb 3. PMID:20130576 doi:10.1038/nature08833

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1. PMID:17603483 doi:10.1038/ng2073

[2] Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7. Epub 2007 Jul 1. PMID:17603482 doi:ng2078

[3] Longoni M, Moncini S, Cisternino M, Morella IM, Ferraiuolo S, Russo S, Mannarino S, Brazzelli V, Coi P, Zippel R, Venturin M, Riva P. Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations. Am J Med Genet A. 2010 Sep;152A(9):2176-84. doi: 10.1002/ajmg.a.33564. PMID:20683980 doi:10.1002/ajmg.a.33564

[4] Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1. PMID:17603483 doi:10.1038/ng2073

[5] Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, Morrice N, Moelling K, Aitken A. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem. 1997 Nov 14;272(46):28882-8. PMID:9360956

[6] Chen J, Fujii K, Zhang L, Roberts T, Fu H. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7783-8. Epub 2001 Jun 26. PMID:11427728 doi:10.1073/pnas.141224398

[7] Broustas CG, Grammatikakis N, Eto M, Dent P, Brautigan DL, Kasid U. Phosphorylation of the myosin-binding subunit of myosin phosphatase by Raf-1 and inhibition of phosphatase activity. J Biol Chem. 2002 Jan 25;277(4):3053-9. Epub 2001 Nov 21. PMID:11719507 doi:10.1074/jbc.M106343200

[8] Ding Q, Gros R, Gray ID, Taussig R, Ferguson SS, Feldman RD. Raf kinase activation of adenylyl cyclases: isoform-selective regulation. Mol Pharmacol. 2004 Oct;66(4):921-8. PMID:15385642 doi:10.1124/mol.66.4.

[9] O'Neill E, Rushworth L, Baccarini M, Kolch W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science. 2004 Dec 24;306(5705):2267-70. PMID:15618521 doi:10.1126/science.1103233

[10] Jin S, Zhuo Y, Guo W, Field J. p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. J Biol Chem. 2005 Jul 1;280(26):24698-705. Epub 2005 Apr 22. PMID:15849194 doi:10.1074/jbc.M413374200

[11] Wang Z, Wade P, Mandell KJ, Akyildiz A, Parkos CA, Mrsny RJ, Nusrat A. Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription factor slug. Oncogene. 2007 Feb 22;26(8):1222-30. Epub 2006 Aug 21. PMID:16924233 doi:10.1038/sj.onc.1209902

[12] Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010 Mar 18;464(7287):431-5. Epub 2010 Feb 3. PMID:20130576 doi:10.1038/nature08833

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3omv | pdb_00003omv

Crystal structure of c-raf (raf-1)

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

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Proteopedia Page Contributors and Editors (what is this?)

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