3zhp

Human MST3 (STK24) in complex with MO25betaHuman MST3 (STK24) in complex with MO25beta

Structural highlights

3zhp is a 4 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:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CB39L_HUMAN] Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1 (By similarity). [STK24_HUMAN] Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The MO25 scaffolding protein operates as critical regulator of a number of STE20 family protein kinases (e.g. MST and SPAK isoforms) as well as pseudokinases (e.g. STRAD isoforms that play a critical role in activating the LKB1 tumour suppressor). To better understand how MO25 interacts and stimulates the activity of STE20 protein kinases, we determined the crystal structure of MST3 catalytic domain (residues 19-289) in complex with full length MO25beta. The structure reveals an intricate web of interactions between MST3 and MO25beta that function to stabilise the kinase domain in a closed, active, conformation even in the absence of ATP or an ATP-mimetic inhibitor. The binding mode of MO25beta is reminiscent of the mechanism by which MO25alpha interacts with the pseudokinase STRADalpha. In particular we identified interface residues Tyr223 of MO25beta and Glu58 and Ile71 of MST3 that when mutated prevent activation of MST3 by MO25beta. These data provide molecular understanding of the mechanism by which MO25 isoforms regulates the activity of STE20 family protein kinases.

Structural insights into the activation of MST3 by MO25.,Mehellou Y, Alessi DR, Macartney TJ, Szklarz M, Knapp S, Elkins JM Biochem Biophys Res Commun. 2013 Feb 15;431(3):604-9. doi:, 10.1016/j.bbrc.2012.12.113. Epub 2013 Jan 4. PMID:23296203^[6]

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

References

↑ Stegert MR, Hergovich A, Tamaskovic R, Bichsel SJ, Hemmings BA. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol Cell Biol. 2005 Dec;25(24):11019-29. PMID:16314523 doi:10.1128/MCB.25.24.11019-11029.2005
↑ Lu TJ, Lai WY, Huang CY, Hsieh WJ, Yu JS, Hsieh YJ, Chang WT, Leu TH, Chang WC, Chuang WJ, Tang MJ, Chen TY, Lu TL, Lai MD. Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (MST3) involves paxillin and protein-tyrosine phosphatase-PEST. J Biol Chem. 2006 Dec 15;281(50):38405-17. Epub 2006 Oct 17. PMID:17046825 doi:10.1074/jbc.M605035200
↑ Chen CB, Ng JK, Choo PH, Wu W, Porter AG. Mammalian sterile 20-like kinase 3 (MST3) mediates oxidative-stress-induced cell death by modulating JNK activation. Biosci Rep. 2009 Sep 16;29(6):405-15. doi: 10.1042/BSR20090096. PMID:19604147 doi:10.1042/BSR20090096
↑ Lorber B, Howe ML, Benowitz LI, Irwin N. Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways. Nat Neurosci. 2009 Nov;12(11):1407-14. doi: 10.1038/nn.2414. Epub 2009 Oct 25. PMID:19855390 doi:10.1038/nn.2414
↑ Lin CY, Wu HY, Wang PL, Yuan CJ. Mammalian Ste20-like protein kinase 3 induces a caspase-independent apoptotic pathway. Int J Biochem Cell Biol. 2010 Jan;42(1):98-105. doi:, 10.1016/j.biocel.2009.09.012. Epub 2009 Sep 25. PMID:19782762 doi:10.1016/j.biocel.2009.09.012
↑ Mehellou Y, Alessi DR, Macartney TJ, Szklarz M, Knapp S, Elkins JM. Structural insights into the activation of MST3 by MO25. Biochem Biophys Res Commun. 2013 Feb 15;431(3):604-9. doi:, 10.1016/j.bbrc.2012.12.113. Epub 2013 Jan 4. PMID:23296203 doi:http://dx.doi.org/10.1016/j.bbrc.2012.12.113

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OCA

[1] Stegert MR, Hergovich A, Tamaskovic R, Bichsel SJ, Hemmings BA. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3. Mol Cell Biol. 2005 Dec;25(24):11019-29. PMID:16314523 doi:10.1128/MCB.25.24.11019-11029.2005

[2] Lu TJ, Lai WY, Huang CY, Hsieh WJ, Yu JS, Hsieh YJ, Chang WT, Leu TH, Chang WC, Chuang WJ, Tang MJ, Chen TY, Lu TL, Lai MD. Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (MST3) involves paxillin and protein-tyrosine phosphatase-PEST. J Biol Chem. 2006 Dec 15;281(50):38405-17. Epub 2006 Oct 17. PMID:17046825 doi:10.1074/jbc.M605035200

[3] Chen CB, Ng JK, Choo PH, Wu W, Porter AG. Mammalian sterile 20-like kinase 3 (MST3) mediates oxidative-stress-induced cell death by modulating JNK activation. Biosci Rep. 2009 Sep 16;29(6):405-15. doi: 10.1042/BSR20090096. PMID:19604147 doi:10.1042/BSR20090096

[4] Lorber B, Howe ML, Benowitz LI, Irwin N. Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways. Nat Neurosci. 2009 Nov;12(11):1407-14. doi: 10.1038/nn.2414. Epub 2009 Oct 25. PMID:19855390 doi:10.1038/nn.2414

[5] Lin CY, Wu HY, Wang PL, Yuan CJ. Mammalian Ste20-like protein kinase 3 induces a caspase-independent apoptotic pathway. Int J Biochem Cell Biol. 2010 Jan;42(1):98-105. doi:, 10.1016/j.biocel.2009.09.012. Epub 2009 Sep 25. PMID:19782762 doi:10.1016/j.biocel.2009.09.012

[6] Mehellou Y, Alessi DR, Macartney TJ, Szklarz M, Knapp S, Elkins JM. Structural insights into the activation of MST3 by MO25. Biochem Biophys Res Commun. 2013 Feb 15;431(3):604-9. doi:, 10.1016/j.bbrc.2012.12.113. Epub 2013 Jan 4. PMID:23296203 doi:http://dx.doi.org/10.1016/j.bbrc.2012.12.113

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