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TitleA cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 9746, Year 2024
Publish dateNov 11, 2024
AuthorsM 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 / Louise J Walport /
PubMed AbstractPeptidylarginine deiminase IV (PADI4, PAD4) deregulation promotes the development of autoimmunity, cancer, atherosclerosis and age-related tissue fibrosis. PADI4 additionally mediates immune ...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 >10 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.
External linksNat Commun / PubMed:39528459 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.6 Å
Structure data

EMDB-19011, PDB-8r8u:
Human PADI4 in complex with cyclic peptide PADI4_3
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-19012, PDB-8r8v:
Human PADI4 in complex with cyclic peptide PADI4_11
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsCYTOSOLIC PROTEIN / PADI4 / peptidyl arginine deiminase / Cyclic Peptide

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