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May 15, 2025
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A precisely positioned MED12 activation helix stimulates CDK8 kinase activity.

Publicated to: Proceedings Of The National Academy Of Sciences Of The United States Of America. 117 (6): 2894-2905 - 2020-02-01 117(6), DOI: 10.1073/pnas.1917635117

Authors: Klatt F; Leitner A; Kim IV; Ho-Xuan H; Schneider EV; Langhammer F; Weinmann R; Müller MR; Huber R; Meister G; Kuhn CD

Affiliations

Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg, 93053 Regensburg, Germany. - Author
Department of Biology, Institute of Molecular Systems Biology, Eidgenössiche Technische Hochschule Zürich, 8093 Zürich, Switzerland. - Author
Gene regulation by Non-coding RNA, Elite Network of Bavaria and University of Bayreuth, 95447 Bayreuth, Germany. - Author
Gene Regulation by Non-Coding RNA, Elite Network of Bavaria and University of Bayreuth, 95447 Bayreuth, Germany; huber@biochem.mpg.de claus.kuhn@uni-bayreuth.de. - Author
Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.; Proteros Biostructures GmbH, 82152 Martinsried, Germany. - Author
Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; huber@biochem.mpg.de claus.kuhn@uni-bayreuth.de.; Center of Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany.; Department of Chemistry, Technical University of Muni - Author
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Abstract

The Mediator kinase module regulates eukaryotic transcription by phosphorylating transcription-related targets and by modulating the association of Mediator and RNA polymerase II. The activity of its catalytic core, cyclin-dependent kinase 8 (CDK8), is controlled by Cyclin C and regulatory subunit MED12, with its deregulation contributing to numerous malignancies. Here, we combine in vitro biochemistry, cross-linking coupled to mass spectrometry, and in vivo studies to describe the binding location of the N-terminal segment of MED12 on the CDK8/Cyclin C complex and to gain mechanistic insights into the activation of CDK8 by MED12. Our data demonstrate that the N-terminal portion of MED12 wraps around CDK8, whereby it positions an "activation helix" close to the T-loop of CDK8 for its activation. Intriguingly, mutations in the activation helix that are frequently found in cancers do not diminish the affinity of MED12 for CDK8, yet likely alter the exact positioning of the activation helix. Furthermore, we find the transcriptome-wide gene-expression changes in human cells that result from a mutation in the MED12 activation helix to correlate with deregulated genes in breast and colon cancer. Finally, functional assays in the presence of kinase inhibitors reveal that binding of MED12 remodels the active site of CDK8 and thereby precludes the inhibition of ternary CDK8 complexes by type II kinase inhibitors. Taken together, our results not only allow us to propose a revised model of how CDK8 activity is regulated by MED12, but also offer a path forward in developing small molecules that target CDK8 in its MED12-bound form.

Keywords

Catalytic domainCcnc protein, humanCdk8Cdk8 protein, humanCyclin cCyclin-dependent kinase 8Enzyme activationHumansKinase inhibitorsMed12Med12 protein, humanMediatorMediator complexMediator kinase moduleProtein bindingProtein conformation, alpha-helicalProtein domains

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Proceedings Of The National Academy Of Sciences Of The United States Of America due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 8/72, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-12-08:

  • Europe PMC: 37

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-08:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 85.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 85 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 72.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).
  • The number of mentions in news outlets: 9 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Germany; Switzerland.