Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation

• Published in: iScience Vol. 27; no. 4; p. 109584
• Main Authors: Villanueva-Cañas, José Luis, Fernandez-Fuentes, Narcis, Saul, Dominik, Kosinsky, Robyn Laura, Teyssier, Catherine, Rogalska, Malgorzata Ewa, Pérez, Ferran Pegenaute, Oliva, Baldomero, Notredame, Cedric, Beato, Miguel, Sharma, Priyanka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.04.2024; Elsevier
• Subjects: Biochemistry; Bioinformatics; Biological sciences; Evolutionary biology; Life Sciences; Molecular biology; Natural sciences; Pharmaceutical sciences; Biological sciences; Biochemistry; Natural sciences; Evolutionary biology; Molecular biology; Bioinformatics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.109584

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. [Display omitted] •Positively evolved residues are mainly in the non-catalytic domain of the PADI2•L162 of PADI2 is a positively evolved residue at the structurally exposed loop•PADI2-L162 mediates PADI2’s effective interaction with the P-TEFb complex•PADI2-L162 dictates cell proliferation and c-MYC transcription Natural sciences; Biological sciences; Biochemistry; Molecular biology; Evolutionary biology; Bioinformatics