Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1

Nicola, G.F. De; Martin, Eva Denise; Chaikuad, A.; Bassi, Rekha; Clark, James E.; Martino, Luigi; Verma, Sharwari; Sicard, Pierre; Tata, Renée; Atkinson, R. Andrew; Knapp, Stefan; Conte, Maria R.; Marber, Michael

doi:10.1038/nsmb.2668

Cited by 94 publications

(139 citation statements)

References 48 publications

(93 reference statements)

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…There are 2 examples of MAPKs whose activation loops are noncanonically activated by MAPK-binding proteins that have been studied using structural approaches. The first is p38␣, which is activated in cardiac myocytes by transforming growth factor beta-activated protein kinase binding protein 1 (Tab1) (32). Similar to that of Ssp2, Tab1 binding activates cis autophosphorylation, yet unlike Ssp2, Tab1 activates the autophosphorylation of both the activation loop T and the Y.…”

Section: Discussionmentioning

confidence: 99%

Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

Tio

Omerza

Phillips

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in Saccharomyces cerevisiae that couples spore morphogenesis to the completion of chromosome segregation. Similar to other MAPKs, Smk1 is controlled by phosphorylation of a threonine (T) and a tyrosine (Y) in its activation loop. However, it is not activated by a dual-specificity MAPK kinase. Instead, T207 in Smk1's activation loop is phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase (Cak1), and Y209 is autophosphorylated in an intramolecular reaction that requires the meiosis-specific protein Ssp2. In this study, we show that Smk1 is catalytically inert unless it is bound by Ssp2. While Ssp2 binding activates Smk1 by a mechanism that is independent of activation loop phosphorylation, binding also triggers autophosphorylation of Y209 in Smk1, which, along with Cak1-mediated phosphorylation of T207, further activates the kinase. Autophosphorylation of Smk1 on Y209 also appears to modify the specificity of the MAPK by suppressing Y kinase and enhancing S/T kinase activity. We also found that the phosphoconsensus motif preference of Ssp2/Smk1 is more extensive than that of other characterized MAPKs. This study therefore defines a novel mechanism of MAPK activation requiring binding of an activator and also shows that MAPKs can be diversified to recognize unique phosphorylation motifs.

show abstract

Section: Discussionmentioning

confidence: 99%

Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

Tio

Omerza

Phillips

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…For example, GSK3β can autophosphorylate on Tyr residues, an activity that is dependent on Hsp90 association 18. Furthermore, p38α autophosphorylation in cells is dependent on association with tumor growth factor‐β‐activated kinase 1/MAP3K7‐binding protein 1 (TAB 1)43. In PKD, autophosphorylation on Ser‐742 in cells seems to be dependent on the association with certain Gα isoforms 44.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase D displays intrinsic Tyr autophosphorylation activity: insights into mechanism and regulation

et al. 2018

View full text Add to dashboard Cite

The protein kinase D (PKD) family is regulated through multi‐site phosphorylation, including autophosphorylation. For example, PKD displays in vivo autophosphorylation on Ser‐742 (and Ser‐738 in vitro) in the activation loop and Ser‐910 in the C‐tail (hPKD1 numbering). In this paper, we describe the surprising observation that PKD also displays in vitro autocatalytic activity towards a Tyr residue in the P + 1 loop of the activation segment. We define the molecular determinants for this unusual activity and identify a Cys residue (C705 in PKD1) in the catalytic loop as of utmost importance. In cells, PKD Tyr autophosphorylation is suppressed through the association of an inhibitory factor. Our findings provide important novel insights into PKD (auto)regulation.

show abstract

“…Despite there being no inhibitor described to bind to this site, there is a crystallographic structure of p38α that shows a fragment of the TAB1 protein bound to it that also occupies the docking groove. 59 Binding of the peptide has effects on the conformation of the protein, so that the N-terminal and C-terminal lobes close up to each other as in the active conformation. Furthermore, the structure shows the activation loop in a conformation different to that found in other nonphosphorylated proteins, which is compatible with a cis autophosphorylation mechanism on the Thr 180 residue.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Identification of Potential Small Molecule Binding Pockets in p38α MAP Kinase

Gómez-Gutiérrez

Rubio-Martínez

Pérez

2017

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Given the essential role played by protein kinases in regulating cellular pathways, their dysregulation can result in the onset and/or progression of various human diseases. Structural analysis of diverse protein kinases suggests that these proteins exhibit a remarkable plasticity that allows them to adopt distinct conformations in response to interactions with other proteins, providing an opportunity for designing allosteric modulators. The present work reports the results of an in silico screening study aimed at identifying novel prospective allosteric binding sites in the paradigmatic p38α MAP kinase. The process was carried out using a protein ensemble generated from a 6 μs accelerated molecular dynamics simulation. The results of this calculation were first used to study the flexibility of the protein using Principal Component Analysis, followed by a Cluster Analysis aimed at producing an ensemble of conformations representative of the sampling process. Representative structures of the diverse clusters were subsequently screened for hot spots using FTMAP. The procedure permitted the identification of diverse allosteric sites of p38α already described in the literature including the DFG pocket, the lipid binding pocket, the DEF site, the docking groove, the CD and ED sites, and the backside site as well as a novel site recently reported: the A-loop regulatory site. Furthermore, the study also permitted the identification of ten novel prospective allosteric sites named NP1 to NP10, involving in most of the cases protein structural elements that control kinase activation including the activation loop, the catalytic loop, the αC helix, the L16 loop, and the glycine-rich loop.

show abstract

Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1

Cited by 94 publications

References 48 publications

Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

Ssp2 Binding Activates the Smk1 Mitogen-Activated Protein Kinase

Protein kinase D displays intrinsic Tyr autophosphorylation activity: insights into mechanism and regulation

Identification of Potential Small Molecule Binding Pockets in p38α MAP Kinase

Contact Info

Product

Resources

About