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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 186 224-33 (2014)
Cited: 13 times
EuropePMC logo PMID: 24746913

Abstract

The tumor suppressor kinase LKB1 and germinal center kinases (GCKs) are key regulators of various cellular functions. The adaptor molecule MO25 not only recruits and activates LKB1 through the pseudokinase STRAD, but also may directly activate GCKs like MST3, MST4, STK25, OSR1 and SPAK. Targeting MO25 in a pathological setting has been recently studied in mouse. Yet the regulatory mechanism of MO25-mediated kinase activation is not fully understood. Here, our structural studies of MO25-related kinases reveal that MO25 binds to and activates GCK kinases or pseudokinase through a unified structural mechanism, featuring an active conformation of the αC helix and A-loop stabilized by MO25. Compared to GCKs that are directly activated by MO25-binding, activation of LKB1 has evolved additional layer of regulatory machinery, i.e., MO25 "activates" the pseudokinase STRAD, which in turn activates LKB1. Importantly, the structures of MO25α-STK25 and MO25α-MST3 determined in this work represent a transition/intermediate state and a fully activated state, respectively during the MO25-mediated kinase activating process.

Articles - 4nzw mentioned but not cited (2)

  1. An allosteric regulation mechanism of Arabidopsis Serine/Threonine kinase 1 (SIK1) through phosphorylation. Mu J, Zhou J, Gong Q, Xu Q. Comput Struct Biotechnol J 20 368-379 (2022)
  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 (5)

  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. STRIPAK complexes in cell signaling and cancer. Shi Z, Jiao S, Zhou Z. Oncogene 35 4549-4557 (2016)
  3. MST kinases in innate immune signaling. Shi Z, Zhou Z. Cell Stress 2 4-13 (2017)
  4. GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond. Mahlapuu M, Caputo M, Xia Y, Cansby E. Hepatol Commun 6 2613-2622 (2022)
  5. Looking lively: emerging principles of pseudokinase signaling. Sheetz JB, Lemmon MA. Trends Biochem Sci 47 875-891 (2022)

Articles citing this publication (6)

  1. Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model. Amrutkar M, Cansby E, Chursa U, Nuñez-Durán E, Chanclón B, Ståhlman M, Fridén V, Mannerås-Holm L, Wickman A, Smith U, Bäckhed F, Borén J, Howell BW, Mahlapuu M. Diabetes 64 2791-2804 (2015)
  2. Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans. Amrutkar M, Kern M, Nuñez-Durán E, Ståhlman M, Cansby E, Chursa U, Stenfeldt E, Borén J, Blüher M, Mahlapuu M. Diabetologia 59 341-353 (2016)
  3. 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)
  4. 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)
  5. 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)
  6. A quantitative transcriptomic analysis of the physiological significance of mTOR signaling in goat fetal fibroblasts. Fu Y, Zheng X, Jia X, Binderiya U, Wang Y, Bao W, Bao L, Zhao K, Fu Y, Hao H, Wang Z. BMC Genomics 17 879 (2016)


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