| Structural highlights
Function
[STK38_HUMAN] Negative regulator of MAP3K1/2 signaling. Converts MAP3K2 from its phosphorylated form to its non-phosphorylated form and inhibits autophosphorylation of MAP3K2.[1] [2] [3] [4]
Publication Abstract from PubMed
The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase domain in its non-phosphorylated state, revealing a fully resolved atypically long activation segment that blocks substrate binding and stabilizes a non-productive position of helix alphaC. Consistent with an auto-inhibitory function, mutations within the activation segment of NDR1 dramatically enhance in vitro kinase activity. Interestingly, NDR1 catalytic activity is further potentiated by MOB1 binding, suggesting that regulation through modulation of the activation segment and by MOB1 binding are mechanistically distinct. Lastly, deleting the auto-inhibitory activation segment of NDR1 causes a marked increase in the association with upstream Hippo pathway components and the Furry scaffold. These findings provide a point of departure for future efforts to explore the cellular functions and the mechanism of NDR1.
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.,Xiong S, Lorenzen K, Couzens AL, Templeton CM, Rajendran D, Mao DYL, Juang YC, Chiovitti D, Kurinov I, Guettler S, Gingras AC, Sicheri F Structure. 2018 Aug 7;26(8):1101-1115.e6. doi: 10.1016/j.str.2018.05.014. Epub, 2018 Jul 5. PMID:29983373[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Millward T, Cron P, Hemmings BA. Molecular cloning and characterization of a conserved nuclear serine(threonine) protein kinase. Proc Natl Acad Sci U S A. 1995 May 23;92(11):5022-6. PMID:7761441
- ↑ Tamaskovic R, Bichsel SJ, Rogniaux H, Stegert MR, Hemmings BA. Mechanism of Ca2+-mediated regulation of NDR protein kinase through autophosphorylation and phosphorylation by an upstream kinase. J Biol Chem. 2003 Feb 28;278(9):6710-8. Epub 2002 Dec 17. PMID:12493777 doi:http://dx.doi.org/10.1074/jbc.M210590200
- ↑ Bichsel SJ, Tamaskovic R, Stegert MR, Hemmings BA. Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein. J Biol Chem. 2004 Aug 20;279(34):35228-35. Epub 2004 Jun 14. PMID:15197186 doi:10.1074/jbc.M404542200
- ↑ Enomoto A, Kido N, Ito M, Morita A, Matsumoto Y, Takamatsu N, Hosoi Y, Miyagawa K. Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). Oncogene. 2008 Mar 20;27(13):1930-8. Epub 2007 Oct 1. PMID:17906693 doi:http://dx.doi.org/10.1038/sj.onc.1210828
- ↑ Xiong S, Lorenzen K, Couzens AL, Templeton CM, Rajendran D, Mao DYL, Juang YC, Chiovitti D, Kurinov I, Guettler S, Gingras AC, Sicheri F. Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. Structure. 2018 Aug 7;26(8):1101-1115.e6. doi: 10.1016/j.str.2018.05.014. Epub, 2018 Jul 5. PMID:29983373 doi:http://dx.doi.org/10.1016/j.str.2018.05.014
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