PXD048807

PXD048807 is an original dataset announced via ProteomeXchange.

Title	A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV (PADI4) regulation
Description	Deregulation of the peptidylarginine deiminase PADI4 promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. Genetic or pharmacological PADI4 inhibition is therapeutically efficacious in mice but no clinically relevant inhibitors exist to date. PADI4 additionally mediates the innate immune response and cellular reprogramming, although the full extent of its physiological roles is not understood. Despite having detailed molecular understanding of PADI4 activation in vitro, we lack understanding of its regulation within cells. Here, we identified a set of potent and selective PADI4 modulators. Using the mRNA-display-based RaPID system, we screened >1012 cyclic peptides for high-affinity, conformation-selective binders of human PADI4. We report PADI4_3, an inhibitor specific for the active conformation; PADI4_7, an inert binder, which we functionalised for the isolation and study of cellular PADI4; and PADI4_11, a first-in-class activator. Using a newly developed method for the quantification of cellular PADI4 activity, we show that PADI4_3 and PADI4_11 can modulate PADI4 activity in cells. Structural studies with PADI4_11 reveal an allosteric binding mode that may reflect the mechanism that promotes activation of PADI4 within cells. This work offers new understanding of PADI4 regulation and a toolkit for the study and modulation of PADI4 across different physiological and pathophysiological contexts.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_12:37:02.488.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Oxley
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-23 08:39:42	ID requested
⏵ 1	2025-05-06 12:37:03	announced

10.1038/s41467-024-53554-1;

Bertran MT, Walmsley R, Cummings T, Aramburu IV, Benton DJ, Mora Molina R, Assalaarachchi J, Chasampalioti M, Swanton T, Joshi D, Federico S, Okkenhaug H, Yu L, Oxley D, Walker S, Papayannopoulos V, Suga H, Christophorou MA, Walport LJ, A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation. Nat Commun, 15(1):9746(2024) [pubmed]

submitter keyword: deiminase, cyclic-peptide, modulator,PADI4

David Oxley
contact affiliation	Babraham Institute Cambridge, UK
contact email	david.oxley@babraham.ac.uk
lab head
David Oxley
contact affiliation	Babraham Institute
contact email	david.oxley@babraham.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048807
     1. Label: PRIDE project
     2. Name: A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV (PADI4) regulation