https://phaidra.vetmeduni.ac.at/o:3896 Cdk6’s functions are critically regulated by its unique C-terminus Schirripa, Alessia Alessia Schirripa 0000-0001-5446-9136 University of Veterinary Medicine Vienna Schöppe, Helge Helge Schöppe Nebenfuehr, Sofie Sofie Nebenfuehr University of Veterinary Medicine Vienna Zojer, Markus Markus Zojer University of Veterinary Medicine Vienna Klampfl, Thorsten Thorsten Klampfl 0000-0002-6666-9773 University of Veterinary Medicine Vienna Kugler, Valentina Valentina Kugler Maw, Belinda S. Belinda S. Maw 0000-0002-1881-0883 University of Veterinary Medicine Vienna Ceylan, Huriye Huriye Ceylan University of Veterinary Medicine Vienna Uras, Iris Z. Iris Z. Uras University of Veterinary Medicine Vienna Scheiblecker, Lisa Lisa Scheiblecker University of Veterinary Medicine Vienna Gamper, Elisabeth Elisabeth Gamper University of Veterinary Medicine Vienna Stelzl, Ulrich Ulrich Stelzl Stefan, Eduard Eduard Stefan Kaserer, Teresa Teresa Kaserer Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna Kollmann, Karoline Karoline Kollmann 0000-0002-7937-4245 University of Veterinary Medicine Vienna MDPI journal article open access eng The vital cell cycle machinery is tightly regulated and alterations of its central signaling hubs are a hallmark of cancer. The activity of CDK6 is controlled by interaction with several partners including cyclins and INK4 proteins, which have been shown to mainly bind to the amino-terminal lobe. We analyzed the impact of CDK6's C-terminus on its functions in a leukemia model, revealing a central role in promoting proliferation. C-terminally truncated Cdk6 (Cdk6 D C) shows reduced nuclear translocation and therefore chromatin interaction and fails to enhance proliferation and disease progression. The combination of proteomic analysis and protein modeling highlights that Cdk6's C-terminus is essential for protein flexibility and for its binding potential to cyclin D, p27 Kip1 and INK4 proteins but not cyclin B. We demonstrate that the C-terminus is a unique and essential part of the CDK6 protein, regulating interaction partner binding and therefore CDK6's functionality. Cyclin-Dependent Kinase Cell-Cycle Structural Basis Crystal-Structure Intrinsic Disorder Protein-Structure Inhibitor Prediction Complex Links http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3896/download 10.1016/j.isci.2024.111697 https://phaidra.vetmeduni.ac.at/o:605 application/pdf iScience issn:2589-0042 VoR iScience 28 6.07 MB 2025