The structures of the kinase domain and UBA domain of MPK38 suggest the activation mechanism for kinase activity

Murine protein serine/threonine kinase 38 (MPK38) is the murine orthologue of human maternal embryonic leucine-zipper kinase (MELK), which belongs to the SNF1/AMPK family. MELK is considered to be a promising drug target for anticancer therapy because overexpression and hyperactivation of MELK is correlated with several human cancers. Activation of MPK38 requires the extended sequence (ExS) containing the ubiquitin-associated (UBA) linker and UBA domain and phosphorylation of the activation loop. However, the activation mechanism of MPK38 is unknown. This paper reports the crystal structure of MPK38 (T167E), which mimics a phosphorylated state of the activation loop, in complex with AMP-PNP. In the MPK38 structure, the UBA linker forces an inward movement of the αC helix. Phosphorylation of the activation loop then induces movement of the activation loop towards the C-lobe and results in interlobar cleft closure. These processes generate a fully active state of MPK38. This structure suggests that MPK38 has a similar molecular mechanism regulating activation as in other kinases of the SNF1/AMPK family.

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ZIP Kinase, a Novel Serine/Threonine Kinase Which Mediates Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.18.3.1642 ◽

1998 ◽

Vol 18 (3) ◽

pp. 1642-1651 ◽

Cited By ~ 157

Author(s):

Taro Kawai ◽

Makoto Matsumoto ◽

Kiyoshi Takeda ◽

Hideki Sanjo ◽

Shizuo Akira

Keyword(s):

Leucine Zipper ◽

Catalytic Domain ◽

Morphological Changes ◽

Kinase Domain ◽

Leucine Zippers ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

C Terminus ◽

Death Associated Protein Kinase ◽

Element Binding Protein

ABSTRACT We have identified a novel serine/threonine kinase, designated ZIP kinase, which mediates apoptosis. ZIP kinase contains a leucine zipper structure at its C terminus, in addition to a kinase domain at its N terminus. ZIP kinase physically binds to ATF4, a member of the activating transcription factor/cyclic AMP-responsive element-binding protein (ATF/CREB) family, through interaction between their leucine zippers. The leucine zipper domain is necessary for the homodimerization of ZIP kinase as well as for the activation of kinase. Immunostaining study showed that ZIP kinase localizes in the nuclei. Overexpression of intact ZIP kinase but not catalytically inactive kinase mutants led to the morphological changes of apoptosis in NIH 3T3 cells, suggesting that the cell death-inducing activity of ZIP kinase depends on its intrinsic kinase activity. Interestingly, the catalytic domain of ZIP kinase is closely related to that of death-associated protein kinase (DAP kinase), which is a mediator of apoptosis induced by gamma interferon. Therefore, both ZIP and DAP kinases represent a novel kinase family, which mediates apoptosis through their catalytic activities.

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SEL-5, A Serine/Threonine Kinase That Facilitates lin-12 Activity in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/153.4.1641 ◽

1999 ◽

Vol 153 (4) ◽

pp. 1641-1654 ◽

Cited By ~ 1

Author(s):

Hanna Fares ◽

Iva Greenwald

Keyword(s):

Cell Fate ◽

Point Mutations ◽

Kinase Domain ◽

Terminal Region ◽

Serine Threonine Kinase ◽

Intracellular Domain ◽

Cell Fate Decisions ◽

Threonine Kinase ◽

Amino Terminal ◽

Fate Decision

Abstract Ligands present on neighboring cells activate receptors of the LIN-12/Notch family by inducing a proteolytic cleavage event that releases the intracellular domain. Mutations that appear to eliminate sel-5 activity are able to suppress constitutive activity of lin-12(d) mutations that are point mutations in the extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered intracellular domain. These results suggest that sel-5 acts prior to or during ligand-dependent release of the intracellular domain. In addition, sel-5 suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can suppress defects in the anchor cell/ventral uterine precursor cell fate decision and a sex myoblast/coelomocyte decision, but cannot suppress defects in two different ventral hypodermal cell fate decisions in hermaphrodites and males. sel-5 encodes at least two proteins, from alternatively spliced mRNAs, that share an amino-terminal region and differ in the carboxy-terminal region. The amino-terminal region contains the hallmarks of a serine/threonine kinase domain, which is most similar to mammalian GAK1 and yeast Pak1p.

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Evidence for Selection at thefusedLocus ofDrosophila virilis

Genetics ◽

10.1093/genetics/155.4.1701 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1701-1709 ◽

Cited By ~ 3

Author(s):

Jorge Vieira ◽

Brian Charlesworth

Keyword(s):

Amino Acid ◽

Aspartic Acid ◽

Kinase Domain ◽

Drosophila Virilis ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Usual Equilibrium ◽

Replacement Site ◽

Fused Gene ◽

Significant Linkage

AbstractThe genomic DNA sequence of a 2.4-kb region of the X-linked developmental gene fused was determined in 15 Drosophila virilis strains. One common replacement polymorphism is observed, where a negatively charged aspartic amino acid is replaced by the noncharged amino acid alanine. This replacement variant is located within the serine/threonine kinase domain of the fused gene and is present in ~50% of the sequences in our sample. Significant linkage disequilibrium is detected around this replacement site, although the fused gene is located in a region of the D. virilis X chromosome that seems to experience normal levels of recombination. In a 600-bp region around the replacement site, all eight alanine sequences are identical; of the six aspartic acid sequences, three are also identical. The occurrence of little or no variation within the aspartic acid and alanine haplotypes, coupled with the presence of several differences between them, is very unlikely under the usual equilibrium neutral model. Our results suggest that the fused alanine haplotypes have recently increased in frequency in the D. virilis population.

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Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x15024747 ◽

2016 ◽

Vol 72 (2) ◽

pp. 129-134 ◽

Cited By ~ 22

Author(s):

John S. Sack ◽

Mian Gao ◽

Susan E. Kiefer ◽

Joseph E. Myers ◽

John A. Newitt ◽

...

Keyword(s):

Crystal Structure ◽

Catalytic Domain ◽

Neurofibrillary Tangle ◽

Binding Pocket ◽

Atp Binding ◽

Activation Loop ◽

Serine Threonine Kinase ◽

Atp Binding Site ◽

Threonine Kinase ◽

Catalytic Loop

Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulate microtubule dynamics. Abnormal activity of MARK4 has been proposed to contribute to neurofibrillary tangle formation in Alzheimer's disease. The crystal structure of the catalytic and ubiquitin-associated domains of MARK4 with a potent pyrazolopyrimidine inhibitor has been determined to 2.8 Å resolution with anRworkof 22.8%. The overall structure of MARK4 is similar to those of the other known MARK isoforms. The inhibitor is located in the ATP-binding site, with the pyrazolopyrimidine group interacting with the inter-lobe hinge region while the aminocyclohexane moiety interacts with the catalytic loop and the DFG motif, forcing the activation loop out of the ATP-binding pocket.

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Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

International Journal of Molecular Sciences ◽

10.3390/ijms20194852 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4852 ◽

Cited By ~ 1

Author(s):

Junjun Wang ◽

Juanjuan Liu ◽

Xinmiao Ji ◽

Xin Zhang

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Activity ◽

Kinase Domain ◽

Serine Threonine Kinase ◽

Cycle Progression ◽

Threonine Kinase ◽

Cellular Processes ◽

Activation Segment ◽

And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

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TheMycobacterium tuberculosis serine/threonine kinase PknL phosphorylates Rv2175c: Mass spectrometric profiling of the activation loop phosphorylation sites and their role in the recruitment of Rv2175c

PROTEOMICS ◽

10.1002/pmic.200700442 ◽

2008 ◽

Vol 8 (3) ◽

pp. 521-533 ◽

Cited By ~ 46

Author(s):

Marc J. Canova ◽

Romain Veyron-Churlet ◽

Isabelle Zanella-Cleon ◽

Martin Cohen-Gonsaud ◽

Alain J. Cozzone ◽

...

Keyword(s):

Mass Spectrometric ◽

Activation Loop ◽

Phosphorylation Sites ◽

Serine Threonine Kinase ◽

Threonine Kinase

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Identification of a Family of Vibrio Type III Secretion System Effectors That Contain a Conserved Serine/Threonine Kinase Domain

mSphere ◽

10.1128/msphere.00599-21 ◽

2021 ◽

Author(s):

N. Plaza ◽

I. M. Urrutia ◽

K. Garcia ◽

M. K. Waldor ◽

C. J. Blondel

Keyword(s):

Type Iii Secretion ◽

Type Iii Secretion System ◽

Kinase Domain ◽

Secretion System ◽

Effector Proteins ◽

Serine Threonine Kinase ◽

Content Type ◽

Threonine Kinase ◽

Type Iii ◽

Infected Cells

Vibrio parahaemolyticus is the leading bacterial cause of seafood-borne gastroenteritis worldwide. The pathogen relies on a type III secretion system to deliver a variety of effector proteins into the cytosol of infected cells to subvert cellular function.

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The mechanism of activation of monomeric B-Raf V600E

10.1101/2021.04.06.438646 ◽

2021 ◽

Author(s):

Ryan C Maloney ◽

Mingzhen Zhang ◽

HYUNBUM JANG ◽

Ruth Nussinov

Keyword(s):

Hydrophobic Interactions ◽

Salt Bridge ◽

Activation Loop ◽

Wild Type ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Oncogenic Mutations ◽

In The Wild ◽

Activation Pathways ◽

The Impact

Oncogenic mutations in the serine/threonine kinase B-Raf, particularly the V600E mutation, are frequent in cancer, making it a major drug target. Although much is known about B-Raf's active and inactive states, questions remain about the mechanism by which the protein changes between these two states. Here, we utilize molecular dynamics to investigate both wild-type and V600E B-Raf to gain mechanistic insights into the impact of the Val to Glu mutation. The results show that the wild-type and mutant follow similar activation pathways involving an extension of the activation loop and an inward motion of the αC-helix. The V600E mutation, however, destabilizes the inactive state by disrupting hydrophobic interactions present in the wild-type structure while the active state is stabilized through the formation of a salt bridge between Glu600 and Lys507. Additionally, when the activation loop is extended, the αC-helix is able to move between an inward and outward orientation as long as the DFG motif adopts a specific orientation. In that orientation Phe595 rotates away from the αC-helix, allowing the formation of a salt bridge between Lys483 and Glu501. These mechanistic insights have implications for the development of new Raf inhibitors.

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The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry

Development ◽

10.1242/dev.127.7.1467 ◽

2000 ◽

Vol 127 (7) ◽

pp. 1467-1475 ◽

Cited By ~ 6

Author(s):

J.L. Watts ◽

D.G. Morton ◽

J. Bestman ◽

K.J. Kemphues

Keyword(s):

Cell Cycle ◽

Kinase Domain ◽

Missense Mutations ◽

Serine Threonine Kinase ◽

Cell Stage ◽

Threonine Kinase ◽

C Elegans ◽

Human Kinase ◽

Early Embryos ◽

Peutz Jeghers Syndrome

During the first cell cycle of Caenorhabditis elegans embryogenesis, asymmetries are established that are essential for determining the subsequent developmental fates of the daughter cells. The maternally expressed par genes are required for establishing this polarity. The products of several of the par genes have been found to be themselves asymmetrically distributed in the first cell cycle. We have identified the par-4 gene of C. elegans, and find that it encodes a putative serine-threonine kinase with similarity to a human kinase associated with Peutz-Jeghers Syndrome, LKB1 (STK11), and a Xenopus egg and embryo kinase, XEEK1. Several strong par-4 mutant alleles are missense mutations that alter conserved residues within the kinase domain, suggesting that kinase activity is essential for PAR-4 function. We find that the PAR-4 protein is present in the gonads, oocytes and early embryos of C. elegans, and is both cytoplasmically and cortically distributed. The cortical distribution begins at the late 1-cell stage, is more pronounced at the 2- and 4-cell stages and is reduced at late stages of embryonic development. We find no asymmetry in the distribution of PAR-4 protein in C. elegans embryos. The distribution of PAR-4 protein in early embryos is unaffected by mutations in the other par genes.

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