1vzo

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The structure of the N-terminal kinase domain of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein

Structural highlights

1vzo is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:BME, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KS6A5_HUMAN Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factors RELA, STAT3 and ETV1/ER81, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression. In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress. In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential. Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors. Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury.[1] [2] [3] [4] [5] [6] [7] [8] [9]

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

Mitogen and stress-activated kinase-1 (MSK1) is a serine/threonine protein kinase that is activated by either p38 or p42ERK MAPKs in response to stress or mitogenic extracellular stimuli. MSK1 belongs to a family of protein kinases that contain two distinct kinase domains in one polypeptide chain. We report the 1.8 A crystal structure of the N-terminal kinase domain of MSK1. The crystal structure reveals a unique inactive conformation with the ATP binding site blocked by the nucleotide binding loop. This inactive conformation is stabilized by the formation of a new three-stranded beta sheet on the N lobe of the kinase domain. The three beta strands come from residues at the N terminus of the kinase domain, what would be the alphaB helix in the active conformation, and the activation loop. The new three-stranded beta sheet occupies a position equivalent to the N terminus of the alphaC helix in active protein kinases.

The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein.,Smith KJ, Carter PS, Bridges A, Horrocks P, Lewis C, Pettman G, Clarke A, Brown M, Hughes J, Wilkinson M, Bax B, Reith A Structure. 2004 Jun;12(6):1067-77. PMID:15274926[10]

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

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See Also

References

  1. ↑ Wiggin GR, Soloaga A, Foster JM, Murray-Tait V, Cohen P, Arthur JS. MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol. 2002 Apr;22(8):2871-81. PMID:11909979
  2. ↑ Janknecht R. Regulation of the ER81 transcription factor and its coactivators by mitogen- and stress-activated protein kinase 1 (MSK1). Oncogene. 2003 Feb 6;22(5):746-55. PMID:12569367 doi:http://dx.doi.org/10.1038/sj.onc.1206185
  3. ↑ Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003 Mar 17;22(6):1313-24. PMID:12628924 doi:http://dx.doi.org/10.1093/emboj/cdg139
  4. ↑ Wierenga AT, Vogelzang I, Eggen BJ, Vellenga E. Erythropoietin-induced serine 727 phosphorylation of STAT3 in erythroid cells is mediated by a MEK-, ERK-, and MSK1-dependent pathway. Exp Hematol. 2003 May;31(5):398-405. PMID:12763138
  5. ↑ Soloaga A, Thomson S, Wiggin GR, Rampersaud N, Dyson MH, Hazzalin CA, Mahadevan LC, Arthur JS. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J. 2003 Jun 2;22(11):2788-97. PMID:12773393 doi:http://dx.doi.org/10.1093/emboj/cdg273
  6. ↑ Zhang Y, Griffin K, Mondal N, Parvin JD. Phosphorylation of histone H2A inhibits transcription on chromatin templates. J Biol Chem. 2004 May 21;279(21):21866-72. Epub 2004 Mar 9. PMID:15010469 doi:http://dx.doi.org/10.1074/jbc.M400099200
  7. ↑ Beck IM, Vanden Berghe W, Vermeulen L, Bougarne N, Vander Cruyssen B, Haegeman G, De Bosscher K. Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-kappaB inhibition. EMBO J. 2008 Jun 18;27(12):1682-93. doi: 10.1038/emboj.2008.95. Epub 2008 May 29. PMID:18511904 doi:http://dx.doi.org/10.1038/emboj.2008.95
  8. ↑ Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998 Aug 3;17(15):4426-41. PMID:9687510 doi:10.1093/emboj/17.15.4426
  9. ↑ New L, Zhao M, Li Y, Bassett WW, Feng Y, Ludwig S, Padova FD, Gram H, Han J. Cloning and characterization of RLPK, a novel RSK-related protein kinase. J Biol Chem. 1999 Jan 8;274(2):1026-32. PMID:9873047
  10. ↑ Smith KJ, Carter PS, Bridges A, Horrocks P, Lewis C, Pettman G, Clarke A, Brown M, Hughes J, Wilkinson M, Bax B, Reith A. The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein. Structure. 2004 Jun;12(6):1067-77. PMID:15274926 doi:10.1016/j.str.2004.02.040

Contents


PDB ID 1vzo

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