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Structure of zebrafish MO25.

ABSTRACT: MO25, a conserved scaffold protein, activates the tumour suppressor LKB1 with the pseudokinase STRAD. MO25 also promotes the activities of the STE20-family kinases MST3, MST4, STK25, SPAK and OSR1. Zebrafish MO25 was purified and crystallized, and a crystal of zebrafish MO25 diffracted to 2.9?Å resolution and belonged to space group P3221, with unit-cell parameters a = b = 156.665, c = 221.251?Å. The structure of zebrafish MO25 was determined by molecular replacement. It is constituted of seven helical repeats. Structural comparison indicates that the overall structures of zebrafish and human MO25 are very similar, suggesting that MO25 has conserved functions in zebrafish. This work provides a structural basis for further functional and evolutionary studies of MO25.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC3758145 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Structure of zebrafish MO25.

Zhang Zhenzhen Z Wang Yicui Y Shi Zhubing Z Zhang Min M

Acta crystallographica. Section F, Structural biology and crystallization communications 20130823 Pt 9

MO25, a conserved scaffold protein, activates the tumour suppressor LKB1 with the pseudokinase STRAD. MO25 also promotes the activities of the STE20-family kinases MST3, MST4, STK25, SPAK and OSR1. Zebrafish MO25 was purified and crystallized, and a crystal of zebrafish MO25 diffracted to 2.9 Å resolution and belonged to space group P3221, with unit-cell parameters a = b = 156.665, c = 221.251 Å. The structure of zebrafish MO25 was determined by molecular replacement. It is constituted of seven ...[more]

PMID: 23989145

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Project description:The myocardium undergoes extensive metabolic and energetic remodeling during the progression of cardiac disease. Central to remodeling are changes in the adenine nucleotide pool. Fluctuations in these pools can activate AMP-activated protein kinase (AMPK), the central regulator of cellular energetics. Binding of AMP to AMPK not only allosterically activates AMPK but also promotes phosphorylation of AMPK by an upstream kinase complex, LKB1/Mo25/STRAD (liver kinase B 1, mouse protein 25, STE-related adaptor protein). AMPK phosphorylation by the LKB1 complex results in a substantial increase in AMPK activity. Molecular targeting by the LKB1 complex depends on subcellular localization and transcriptional expression. Yet, little is known about the ability of the LKB1 complex to modulate targeting of AMPK after activation. Accordingly, we hypothesized that differing stoichiometric ratios of LKB1 activator complex to AMPK would uniquely impact myofilament function. Demembranated rat cardiac trabeculae were incubated with varying ratios of the LKB1 complex to AMPK or the LKB1 complex alone. After incubation, we measured the Ca(2+) sensitivity of tension, rate constant for tension redevelopment, maximum tension generation, length-dependent activation, cooperativity, and sarcomeric protein phosphorylation status. We found that the Ca(2+) sensitivity of tension and cross-bridge dynamics were dependent on the LKB1 complex/AMPK ratio. We also found that the LKB1 complex desensitizes and suppresses myofilament function independently of AMPK. A phospho-proteomic analysis of myofilament proteins revealed site-specific changes in cardiac Troponin I (cTnI) phosphorylation, as well as a unique distribution of cTnI phosphospecies that were dependent on the LKB1 complex/ AMPK ratio. Fibers treated with the LKB1 complex alone did not alter cTnI phosphorylation or phosphospecies distribution. However, LKB1 complex treatment independent of AMPK increased phosphorylation of myosin-binding protein C. Therefore, we conclude that the LKB1/AMPK signaling axis is able to alter muscle function through multiple mechanisms.

Dataset Information

Structure of zebrafish MO25.

Publications

Structure of zebrafish MO25.

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