Structural Comparison of Human Mammalian Ste20-Like Kinases

Record, Christopher J; Chaikuad, A.; Rellos, P.; Das, Sumit Kumar; Pike, Ashley C.W.; Fedorov, O.; Marsden, Brian D.; Knapp, Stefan; Lee, Wen‐Hwa

doi:10.1371/journal.pone.0011905

Cited by 46 publications

(51 citation statements)

References 59 publications

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“…GST pull-down and immunoprecipitation experiments confirmed that the Hpo N-terminal kinase domain (amino acids 1-342) interacts with itself or endogenous Hpo (supplemental Fig. S3, A and B), a result in agreement with the recent crystallographic studies of Mst1, Mst3, and Mst4 kinase domains (27). These observations suggested that Drosophila Hpo N-terminal kinase domains indeed form homodimers facilitated by the upstream regulators.…”

Section: N-terminal Homodimerization Of Hpo Is Critical For Its Kinassupporting

confidence: 88%

“…Because phosphorylation of Hpo at Thr-195 has been implicated in the regulation of Hpo kinase activity (62), and the corresponding residue in Mst1, Thr-183, has been identified to be the autophosphorylation site (36), Thr-195 may be the autophosphorylation site of Drosophila Hpo. In addition, the reported Mst1 structure presumably possesses an active conformation, in which Thr-177 and Thr-183 are kept in phosphorylated status (27). To prevent phosphorylation, we then mutated their corresponding sites in Hpo (Thr-189 and Thr-195) to Ala (referred to as T189A and T195A).…”

Section: N-terminal Homodimerization Of Hpo Is Critical For Its Kinasmentioning

confidence: 99%

“…Mammalian Mst1 and Mst2, which belong to the germinal center kinase subfamily (GCKII), are closely related to Drosophila Hpo, sharing 76% sequence identity (27). Both kinases have an N-terminal catalytic domain and a C-terminal coiled coil interaction motif called the SARAH (for Sav/Rassf/Hpo) domain that mediates self-association as well as association with other SARAH domain-containing proteins (28,29).…”

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confidence: 99%

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Dimerization and Cytoplasmic Localization Regulate Hippo Kinase Signaling Activity in Organ Size Control

Jin

Dong

et al. 2012

Journal of Biological Chemistry

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Background: Hippo plays critical roles in organ size control, and the regulation of its activity remains poorly characterized. Results: N-terminal dimerization of Hpo is critical for Hippo kinase activity. The Hippo C-terminal half promotes cytoplasmic localization and activity of Hippo. Conclusion: Dimerization and nucleocytoplasmic translocation of Hippo are crucial for its biological function. Significance: Dimerization and cytoplasmic localization regulate Hippo activity.

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Section: N-terminal Homodimerization Of Hpo Is Critical For Its Kinassupporting

confidence: 88%

Section: N-terminal Homodimerization Of Hpo Is Critical For Its Kinasmentioning

confidence: 99%

mentioning

confidence: 99%

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Dimerization and Cytoplasmic Localization Regulate Hippo Kinase Signaling Activity in Organ Size Control

Jin

Dong

et al. 2012

Journal of Biological Chemistry

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“…This strain displayed wild-type growth characteristics, confirming the full functionality of the modified kinase. Phosphate incorporation in precipitated HA-POD6 in vitro indicated that we were able to obtain active GC kinase that did undergo autophosphorylation, as described for other GC kinases (29,48,50). If POD6 functions upstream of COT1, we reasoned that preincubation of precipitated myc-COT1 with precipitated HA-POD6 should stimulate the in vitro activity of COT1.…”

Section: (D337a) Plus His-3mentioning

confidence: 78%

Hydrophobic Motif Phosphorylation Coordinates Activity and Polar Localization of the Neurospora crassa Nuclear Dbf2-Related Kinase COT1

Maerz

Dettmann

Seiler

2012

Molecular and Cellular Biology

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Nuclear Dbf2p-related (NDR) kinases and associated proteins are recognized as a conserved network that regulates eukaryotic cell polarity. NDR kinases require association with MOB adaptor proteins and phosphorylation of two conserved residues in the activation segment and hydrophobic motif for activity and function. We demonstrate that the Neurospora crassa NDR kinase COT1 forms inactive dimers via a conserved N-terminal extension, which is also required for the interaction of the kinase with MOB2 to generate heterocomplexes with basal activity. Basal kinase activity also requires autophosphorylation of the COT1-MOB2 complex in the activation segment, while hydrophobic motif phosphorylation of COT1 by the germinal center kinase POD6 fully activates COT1 through induction of a conformational change. Hydrophobic motif phosphorylation is also required for plasma membrane association of the COT1-MOB2 complex. MOB2 further restricts the membrane-associated kinase complex to the hyphal apex to promote polar cell growth. These data support an integrated mechanism of NDR kinase regulation in vivo, in which kinase activation and cellular localization of COT1 are coordinated by dual phosphorylation and interaction with MOB2. N uclear Dbf2p-related (NDR) kinases represent a subfamily of AGC (protein kinase A [PKA], PKG, and PKC-like) kinases. These kinases share structural similarities and require (auto) phosphorylation of a conserved Ser/Thr residue within the activation segment of the kinase domain for their activity. Phosphorylation of the activation segment leads to conformational changes that are required for basal enzymatic activity (31,42,45). Activation of AGC kinases also requires a second phosphorylation event or the permanent presence of an acidic residue in a hydrophobic motif that is located 45 to 60 residues C-terminal of the catalytic kinase domain in addition to phosphorylation of the activation loop (7,33,34). Germinal center (GC) kinases, a subfamily of Ste20-type kinases (10, 47), are involved in phosphorylation of this hydrophobic motif (9,12,26,55,57,64). The phosphorylated motif interacts with a hydrophobic pocket in the N-terminal lobe of the kinase domain and induces/stabilizes the reconfiguration of the bilobal kinase structure (6,13,16,60). Thus, both the phosphorylated activation segment and the phosphorylated hydrophobic motif are required for achieving the active conformation of the kinase (31,42,45,64). Nevertheless, the chronology of these two phosphorylation events depends on the specific kinase, and either phosphorylation of the activation loop or hydrophobic motif phosphorylation can occur as the first step of kinase activation (4,18,54,56).Most AGC kinases contain functional domains other than the kinase core that are involved in regulating kinase activity and in vivo function. Important for NDR kinases are MOB coactivator proteins, which bind to the conserved N terminus of these kinases and are involved in their initial activation, presumably by promoting autophosphorylation of their act...

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“…The statistics of data processing are summarized in Table 1. We are currently attempting to solve the structure of AtMAP4Kalpha2-KD using molecular-replacement calculations with the atomic coordinates of MST4 (PDB entry 3ggf; Record et al, 2010) as a search model. In parallel with crystallographic studies, kinase assays are being carried out in order to shed light on the kinase activity of the AtMAP4K-alpha2-KD.…”

Section: Resultsmentioning

confidence: 99%

Cloning, expression, purification, crystallization and preliminary crystallographic analysis of the kinase domain of AtMAP4Kalpha2 fromArabidopsis thaliana

Shen

et al. 2013

Acta Cryst Sect F

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Arabidopsis thaliana (At) MAP4Kalpha2, a member of the Ste20/PAK-like protein kinase family, is an essential component of the septum initiation network involved in cell division. To better understand the mode of action of AtMAP4Kalpha2, a structural biology approach has been pursued. In this study, the kinase domain of AtMAP4Kalpha2 was cloned, expressed, purified and crystallized. The crystals diffracted to 1.9 Å resolution and belonged to space group C222 1 , with unit-cell parameters a = 55.27, b = 82.93, c = 133.15 Å .

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Structural Comparison of Human Mammalian Ste20-Like Kinases

Cited by 46 publications

References 59 publications

Dimerization and Cytoplasmic Localization Regulate Hippo Kinase Signaling Activity in Organ Size Control

Dimerization and Cytoplasmic Localization Regulate Hippo Kinase Signaling Activity in Organ Size Control

Hydrophobic Motif Phosphorylation Coordinates Activity and Polar Localization of the Neurospora crassa Nuclear Dbf2-Related Kinase COT1

Cloning, expression, purification, crystallization and preliminary crystallographic analysis of the kinase domain of AtMAP4Kalpha2 fromArabidopsis thaliana

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