Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422400806X |
| _version_ | 1827287415147986944 |
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| author | 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 |
| author_facet | 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 |
| author_sort | José Luis Villanueva-Cañas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T10:57:57Z |
| format | Article |
| id | doaj.art-dcca59766b1249ce963e9b46e07add27 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-24T10:57:57Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-dcca59766b1249ce963e9b46e07add272024-04-12T04:45:41ZengElsevieriScience2589-00422024-04-01274109584Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulationJosé Luis Villanueva-Cañas0Narcis Fernandez-Fuentes1Dominik Saul2Robyn Laura Kosinsky3Catherine Teyssier4Malgorzata Ewa Rogalska5Ferran Pegenaute Pérez6Baldomero Oliva7Cedric Notredame8Miguel Beato9Priyanka Sharma10Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, SpainInstitute of Biological, Environmental and Rural Sciences, Aberystwyth University, Aberystwyth, Ceredigion, United KingdomDivision 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, GermanyRobert Bosch Center for Tumor Diseases, Stuttgart, GermanyInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Institut Du Cancer de Montpellier (ICM), F-34298 Montpellier, FranceCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, SpainLive-Cell Structural Biology Laboratory, Department of Medicine and Life Sciences, E-08005 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, SpainUniversitat Pompeu Fabra (UPF), Barcelona, Spain; Structural Bioinformatics Laboratory (GRIB-IMIM), Department of Medicine and Life Sciences, E-08003 Barcelona, SpainCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, SpainCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, SpainInstitut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S258900422400806XNatural sciencesBiological sciencesBiochemistryMolecular biologyEvolutionary biologyBioinformatics |
| spellingShingle | 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 Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation iScience Natural sciences Biological sciences Biochemistry Molecular biology Evolutionary biology Bioinformatics |
| title | Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation |
| title_full | Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation |
| title_fullStr | Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation |
| title_full_unstemmed | Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation |
| title_short | Evolutionary analysis reveals the role of a non-catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation |
| title_sort | evolutionary analysis reveals the role of a non catalytic domain of peptidyl arginine deiminase 2 in transcriptional regulation |
| topic | Natural sciences Biological sciences Biochemistry Molecular biology Evolutionary biology Bioinformatics |
| url | http://www.sciencedirect.com/science/article/pii/S258900422400806X |
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