3zhp
From Proteopedia
Human MST3 (STK24) in complex with MO25beta
Structural highlights
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 PubMedThe 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. See AlsoReferences
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