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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 431 604-9 (2013)
Cited: 19 times
EuropePMC logo PMID: 23296203

Abstract

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 MO25β. The structure reveals an intricate web of interactions between MST3 and MO25β 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 MO25β is reminiscent of the mechanism by which MO25α interacts with the pseudokinase STRADα. In particular we identified interface residues Tyr223 of MO25β and Glu58 and Ile71 of MST3 that when mutated prevent activation of MST3 by MO25β. These data provide molecular understanding of the mechanism by which MO25 isoforms regulates the activity of STE20 family protein kinases.

Articles - 3zhp mentioned but not cited (2)

  1. 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 431 604-609 (2013)
  2. Dimerization and autophosphorylation of the MST family of kinases are controlled by the same set of residues. Weingartner KA, Tran T, Tripp KW, Kavran JM. Biochem J 480 1165-1182 (2023)


Reviews citing this publication (7)

  1. The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Alessi DR, Zhang J, Khanna A, Hochdörfer T, Shang Y, Kahle KT. Sci Signal 7 re3 (2014)
  2. MST kinases in development and disease. Thompson BJ, Sahai E. J Cell Biol 210 871-882 (2015)
  3. SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein-protein interactions. Sugden PH, McGuffin LJ, Clerk A. Biochem J 454 13-30 (2013)
  4. The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective. Xiao Y, Dong J. Cancers (Basel) 13 6214 (2021)
  5. Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport. Zhang J, Karimy JK, Delpire E, Kahle KT. Expert Opin Ther Targets 21 795-804 (2017)
  6. GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond. Mahlapuu M, Caputo M, Xia Y, Cansby E. Hepatol Commun 6 2613-2622 (2022)
  7. Molecular mechanisms involved in regulating protein activity and biological function of MST3. Qiu J, Xiong J, Jiang L, Wang X, Zhang K, Yu H. Cell Div 18 8 (2023)

Articles citing this publication (10)

  1. Discovery of Diverse Small-Molecule Inhibitors of Mammalian Sterile20-like Kinase 3 (MST3). Olesen SH, Zhu JY, Martin MP, Schönbrunn E. ChemMedChem 11 1137-1144 (2016)
  2. Domain-Swapping Switch Point in Ste20 Protein Kinase SPAK. Taylor CA, Juang YC, Earnest S, Sengupta S, Goldsmith EJ, Cobb MH. Biochemistry 54 5063-5071 (2015)
  3. Structural insights into regulatory mechanisms of MO25-mediated kinase activation. Hao Q, Feng M, Shi Z, Li C, Chen M, Wang W, Zhang M, Jiao S, Zhou Z. J Struct Biol 186 224-233 (2014)
  4. Cell cycle regulated interaction of a yeast Hippo kinase and its activator MO25/Hym1. Hsu J, Weiss EL. PLoS One 8 e78334 (2013)
  5. STK3 is a therapeutic target for a subset of acute myeloid leukemias. Camgoz A, Paszkowski-Rogacz M, Satpathy S, Wermke M, Hamann MV, von Bonin M, Choudhary C, Knapp S, Buchholz F. Oncotarget 9 25458-25473 (2018)
  6. Structural and biochemical insights into the activation mechanisms of germinal center kinase OSR1. Li C, Feng M, Shi Z, Hao Q, Song X, Wang W, Zhao Y, Jiao S, Zhou Z. J Biol Chem 289 35969-35978 (2014)
  7. Control of Plant Cell Growth and Proliferation by MO25A, a Conserved Major Component of the Mammalian Sterile 20-Like Kinase Pathway. Ta KN, Yoshida MW, Tezuka T, Shimizu-Sato S, Nosaka-Takahashi M, Toyoda A, Suzuki T, Goshima G, Sato Y. Plant Cell Physiol 64 336-351 (2023)
  8. Letter Frameshift Mutations of CAB39L, an Activator of LKB1 Tumor Suppressor, in Gastric and Colorectal Cancers. Choi MR, An CH, Yoo NJ, Lee SH. Pathol Oncol Res 22 225-226 (2016)
  9. NDR kinase tricornered genetically interacts with Ccm3 and metabolic enzymes in Drosophila melanogaster tracheal development. Hudson J, Paul S, Veraksa A, Ghabrial A, Harvey KF, Poon C. G3 (Bethesda) 13 jkad013 (2023)
  10. Structure of zebrafish MO25. Zhang Z, Wang Y, Shi Z, Zhang M. Acta Crystallogr Sect F Struct Biol Cryst Commun 69 989-993 (2013)


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