A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation

M. Teresa Bertran, Robert Walmsley, Thomas Cummings, Iker Valle Aramburu, Donald J. Benton, Rocio Mora Molina, Jayalini Assalaarachchi, Maria Chasampalioti, Tessa Swanton, Dhira Joshi, Stefania Federico, Hanneke Okkenhaug, Lu Yu, David Oxley, Simon Walker, Venizelos Papayannopoulos, Hiroaki Suga, Maria A. Christophorou () and Louise J. Walport ()
Additional contact information
M. Teresa Bertran: The Francis Crick Institute
Robert Walmsley: The Babraham Institute
Thomas Cummings: The Babraham Institute
Iker Valle Aramburu: The Francis Crick Institute
Donald J. Benton: The Francis Crick Institute
Rocio Mora Molina: The Babraham Institute
Jayalini Assalaarachchi: The Babraham Institute
Maria Chasampalioti: The Babraham Institute
Tessa Swanton: The Francis Crick Institute
Dhira Joshi: The Francis Crick Institute
Stefania Federico: The Francis Crick Institute
Hanneke Okkenhaug: The Babraham Institute
Lu Yu: The Babraham Institute
David Oxley: The Babraham Institute
Simon Walker: The Babraham Institute
Venizelos Papayannopoulos: The Francis Crick Institute
Hiroaki Suga: Bunkyo-ku
Maria A. Christophorou: The Babraham Institute
Louise J. Walport: The Francis Crick Institute

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Peptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune responses and cellular reprogramming, although the full extent of its physiological roles is unexplored. Despite detailed molecular knowledge of PADI4 activation in vitro, we lack understanding of its regulation within cells, largely due to a lack of appropriate systems and tools. Here, we develop and apply a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screen >1012 cyclic peptides for high-affinity, conformation-selective binders. We report PADI4_3, a cell-active inhibitor specific for the active conformation of PADI4; PADI4_7, an inert binder, which we functionalise for the isolation and study of cellular PADI4; and PADI4_11, a cell-active PADI4 activator. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes cellular PADI4 activation. This work contributes to our understanding of PADI4 regulation and provides a toolkit for the study and modulation of PADI4 across (patho)physiological contexts.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53554-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53554-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53554-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().