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PreprintCited by 6Cancer-related gene regulationGenomics and Chromatin DynamicsProtein Structure and Dynamics

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

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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·2022·iScience
DOI 10.1101/2022.09.19.508513PMC PMC11016909

Preprint — published as 10.1016/j.isci.2024.109584

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Abstract

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 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. Significance Statement: Here we use a systematic evolutionary analysis to identify positively selected residues in the non-catalytic domain of PADI2 and link the positive selection of key residues to a role in transcription. Specifically, a structurally exposed loop in the PADI2 middle domain encompasses the positively selected residue L162 which is linked to transcription and cellular proliferation. This loop contributes to PADI2 interaction with the P-TEFb complex and cellular proliferation. Our results showcase the utility of combining evolutionary and experimental approaches to dissect the evolution of essential functional processes.

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Metadata

Authors
Villanueva-Cañas, J. L., Fernandez-Fuentes, N., Saul, D., Kosinsky, R. L., Teyssier, C., Rogalska, M. E., Pérez, F. P., Oliva, B., Notredame, C., Beato, M., & Sharma, P.
Affiliations
  • Mayo Clinic (US)
  • Robert Bosch Hospital (DE)
  • Inserm (FR)
  • Barcelona Institute of Science and Technology (ES)
  • Universitat Pompeu Fabra (ES)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Sharma, Priyanka
ORCID
Venue
iScience
Publisher
openRxiv
Published
2022-09-19
Volume
27
Issue
4
Pages
109584-109584
ISSN
2589-0042 (ISSN-L)
DOI
10.1101/2022.09.19.508513
PMC
PMC11016909
OpenAlex
W4393236727
Cited by
6
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 1
FWCI
0.68
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • iScience (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • SSRN Electronic Journal (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Research Foundation (ARCPJA22021050003683)
  • Agence Nationale de la Recherche (ANR-21-CE12, ANR-21-CE12-0010)
  • Institut National de la Santé et de la Recherche Médicale (U1194SHA)
  • Centre National de la Recherche Scientifique
  • Cancéropôle Grand Ouest (R21031FF)
  • European Research Council (609989)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
PAD2, citrullination, positive selection, non-catalytic domains, P-TEFb, transcription elongation, c-Myc, cyclin B1, oncogene transcription, protein-protein interaction, tumor progression, cell proliferation

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