2clq

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Structure of mitogen-activated protein kinase kinase kinase 5Structure of mitogen-activated protein kinase kinase kinase 5

Structural highlights

2clq is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[M3K5_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

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

Apoptosis signal-regulating kinase 1 (ASK1) plays an essential role in stress and immune response and has been linked to the development of several diseases. Here, we present the structure of the human ASK1 catalytic domain in complex with staurosporine. Analytical ultracentrifugation (AUC) and crystallographic analysis showed that ASK1 forms a tight dimer (K(d) approximately 0.2 microM) interacting in a head-to-tail fashion. We found that the ASK1 phosphorylation motifs differ from known ASK1 phosphorylation sites but correspond well to autophosphorylation sites identified by mass spectrometry. Reporter gene assays showed that all three identified in vitro autophosphorylation sites (Thr813, Thr838, Thr842) regulate ASK1 signaling, but site-directed mutants showed catalytic activities similar to wild-type ASK1, suggesting a regulatory mechanism independent of ASK1 kinase activity. The determined high-resolution structure of ASK1 and identified ATP mimetic inhibitors will provide a first starting point for the further development of selective inhibitors.

Structural and functional characterization of the human protein kinase ASK1.,Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Muller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S Structure. 2007 Oct;15(10):1215-26. PMID:17937911[18]

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

See Also

References

  1. ↑ Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, Zukowski M, Yao Z. Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem. 1996 Dec 6;271(49):31607-11. PMID:8940179
  2. ↑ Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997 Jan 3;275(5296):90-4. PMID:8974401
  3. ↑ Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998 May 1;17(9):2596-606. PMID:9564042 doi:10.1093/emboj/17.9.2596
  4. ↑ Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell. 1998 Sep;2(3):389-95. PMID:9774977
  5. ↑ Zhang L, Chen J, Fu H. Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8511-5. PMID:10411906
  6. ↑ Hatai T, Matsuzawa A, Inoshita S, Mochida Y, Kuroda T, Sakamaki K, Kuida K, Yonehara S, Ichijo H, Takeda K. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. J Biol Chem. 2000 Aug 25;275(34):26576-81. PMID:10849426 doi:10.1074/jbc.M003412200
  7. ↑ Liu H, Nishitoh H, Ichijo H, Kyriakis JM. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol. 2000 Mar;20(6):2198-208. PMID:10688666
  8. ↑ Morita K, Saitoh M, Tobiume K, Matsuura H, Enomoto S, Nishitoh H, Ichijo H. Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. EMBO J. 2001 Nov 1;20(21):6028-36. PMID:11689443 doi:10.1093/emboj/20.21.6028
  9. ↑ Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K. Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. J Biol Chem. 2001 Jan 12;276(2):999-1004. PMID:11029458 doi:10.1074/jbc.M003425200
  10. ↑ Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001 Feb;21(3):893-901. PMID:11154276 doi:10.1128/MCB.21.3.893-901.2001
  11. ↑ Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S, Ninomiya-Tsuji J, Matsumoto K, Ichijo H. Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep. 2004 Feb;5(2):161-6. Epub 2004 Jan 16. PMID:14749717 doi:10.1038/sj.embor.7400072
  12. ↑ Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer. J Cell Physiol. 2002 Apr;191(1):95-104. PMID:11920685 doi:10.1002/jcp.10080
  13. ↑ Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng JQ. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. J Biol Chem. 2003 Jun 27;278(26):23432-40. Epub 2003 Apr 15. PMID:12697749 doi:10.1074/jbc.M302674200
  14. ↑ Subramanian RR, Zhang H, Wang H, Ichijo H, Miyashita T, Fu H. Interaction of apoptosis signal-regulating kinase 1 with isoforms of 14-3-3 proteins. Exp Cell Res. 2004 Apr 1;294(2):581-91. PMID:15023544 doi:10.1016/j.yexcr.2003.12.009
  15. ↑ Goldman EH, Chen L, Fu H. Activation of apoptosis signal-regulating kinase 1 by reactive oxygen species through dephosphorylation at serine 967 and 14-3-3 dissociation. J Biol Chem. 2004 Mar 12;279(11):10442-9. Epub 2003 Dec 19. PMID:14688258 doi:10.1074/jbc.M311129200
  16. ↑ Noguchi T, Takeda K, Matsuzawa A, Saegusa K, Nakano H, Gohda J, Inoue J, Ichijo H. Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death. J Biol Chem. 2005 Nov 4;280(44):37033-40. Epub 2005 Aug 29. PMID:16129676 doi:10.1074/jbc.M506771200
  17. ↑ Zhao Y, Conze DB, Hanover JA, Ashwell JD. Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling. J Biol Chem. 2007 Mar 16;282(11):7777-82. Epub 2007 Jan 12. PMID:17220297 doi:10.1074/jbc.M609146200
  18. ↑ Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Muller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S. Structural and functional characterization of the human protein kinase ASK1. Structure. 2007 Oct;15(10):1215-26. PMID:17937911 doi:10.1016/j.str.2007.08.011

2clq, resolution 2.30Å

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