iScience application/pdf Cdk6’s functions are critically regulated by its unique C-terminus Text Wissenschaftlicher Artikel http://creativecommons.org/licenses/by/4.0/ 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 Text journal article doi:10.1016/j.isci.2024.111697 Alessia Schirripa Helge Schöppe Sofie Nebenfuehr Markus Zojer Thorsten Klampfl Valentina Kugler Belinda S. Maw Huriye Ceylan Iris Z. Uras Lisa Scheiblecker Elisabeth Gamper Ulrich Stelzl Eduard Stefan Teresa Kaserer Veronika Sexl Karoline Kollmann eng MDPI 2025 © 2025 The Authors open access https://phaidra.vetmeduni.ac.at/o:3896