2. Academic Validation
  3. Structural basis of the cyclin Y/14-3-3 protein-mediated activation of CDK16

Structural basis of the cyclin Y/14-3-3 protein-mediated activation of CDK16

  • Nat Commun. 2026 Mar 20;17(1):4262. doi: 10.1038/s41467-026-70778-5.
Klara Kohoutova 1 2,  Dalibor Kosek 2,  Adam Brzezina 1,  Karolina Honzejkova 1,  Veronika Obsilova 3,  Tomas Obsil 4 5
Affiliations

Affiliations

  • 1 Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
  • 2 Institute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech Republic.
  • 3 Institute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech Republic. [email protected].
  • 4 Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic. [email protected].
  • 5 Institute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech Republic. [email protected].
PMID: 41857027 DOI: 10.1038/s41467-026-70778-5
Abstract

Cyclin-dependent protein kinase 16 (CDK16) regulates both physiological and pathological processes, including Autophagy, spermatogenesis and Cancer. Unlike Other CDKs, CDK16 is regulated by an unclear mechanism involving phosphorylated cyclin Y (CCNY) in complex with 14-3-3 proteins rather than CCNY alone. The present study aims at elucidating this mechanism by structurally characterizing CDK16 in complex with CCNY and 14-3-3 using several biophysical techniques. As shown by cryo-EM analysis and hydrogen/deuterium exchange coupled to mass spectrometry, 14-3-3 binding modulates the conformation of a key moiety of the CDK binding surface of CCNY, thereby enabling CDK16 activation. CDK16 interacts with the cyclin box of CCNY, while 14-3-3 provides additional contacts, including with the activation segment of CDK16. CDK16 activation also requires interactions of CCNY with the N-terminal extension of CDK16. These findings not only clarify the role of CCNY and 14-3-3 in CDK16 activation but also highlight the potential of targeting CDK16 protein-protein interactions for Cancer therapy.

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