Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation
José Luis Villanueva-Cañas,
Narcis Fernandez-Fuentes,
Dominik Saul,
Robyn Laura Kosinsky,
Catherine Teyssier,
Malgorzata Ewa Rogalska,
Ferran Pegenaute Pérez,
Baldomero Oliva,
Cedric Notredame,
Miguel Beato,
Priyanka Sharma
Affiliations
José Luis Villanueva-Cañas
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain
Narcis Fernandez-Fuentes
Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, Ceredigion, United Kingdom
Dominik Saul
Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA; Department of Trauma and Reconstructive Surgery, BG Clinic, University of Tübingen, Tübingen, Germany
Robyn Laura Kosinsky
Robert Bosch Center for Tumor Diseases, Stuttgart, Germany
Catherine Teyssier
Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Institut Du Cancer de Montpellier (ICM), F-34298 Montpellier, France
Malgorzata Ewa Rogalska
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain
Ferran Pegenaute Pérez
Live-Cell Structural Biology Laboratory, Department of Medicine and Life Sciences, E-08005 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
Baldomero Oliva
Universitat Pompeu Fabra (UPF), Barcelona, Spain; Structural Bioinformatics Laboratory (GRIB-IMIM), Department of Medicine and Life Sciences, E-08003 Barcelona, Spain
Cedric Notredame
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
Miguel Beato
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
Priyanka Sharma
Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France; Corresponding author
Summary: Peptidyl arginine deiminases (PADIs) catalyze protein citrullination, a post-translational conversion of arginine to citrulline. The most widely expressed member of this family, PADI2, regulates cellular processes that impact several diseases. We hypothesized that we could gain new insights into PADI2 function through a systematic evolutionary and structural analysis. Here, we identify 20 positively selected PADI2 residues, 16 of which are structurally exposed and maintain PADI2 interactions with cognate proteins. Many of these selected residues reside in non-catalytic regions of PADI2. We validate the importance of a prominent loop in the middle domain that encompasses PADI2 L162, a residue under positive selection. This site is essential for interaction with the transcription elongation factor (P-TEFb) and mediates the active transcription of the oncogenes c-MYC, and CCNB1, as well as impacting cellular proliferation. These insights could be key to understanding and addressing the role of the PADI2 c-MYC axis in cancer progression.
