Back
Full-text
Journal article

Allosteric activation of MALT1 by its ubiquitin-binding Ig3 domain.

  • Schairer R Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
  • Hall G Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom.
  • Zhang M Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
  • Cowan R Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom.
  • Baravalle R Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom.
  • Muskett FW Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom.
  • Coombs PJ LifeArc, Accelerator Building, Open Innovation Campus, SG1 2FX Stevenage, United Kingdom.
  • Mpamhanga C LifeArc, Accelerator Building, Open Innovation Campus, SG1 2FX Stevenage, United Kingdom.
  • Hale LR LifeArc, Accelerator Building, Open Innovation Campus, SG1 2FX Stevenage, United Kingdom.
  • Saxty B LifeArc, Accelerator Building, Open Innovation Campus, SG1 2FX Stevenage, United Kingdom.
  • Iwaszkiewicz J Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  • Décaillet C Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
  • Perroud M Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
  • Carr MD Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom; mdc12@leicester.ac.uk Margot.ThomeMiazza@unil.ch.
  • Thome M Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; mdc12@leicester.ac.uk Margot.ThomeMiazza@unil.ch.
Show more…
  • 2020-01-26
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2020
T cell
protease
signaling
structure
ubiquitin
Allosteric Regulation
HEK293 Cells
Humans
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Mutation
Protein Binding
Protein Domains
Ubiquitin
Ubiquitination
English The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/186366
Statistics
Document views: 46 File downloads:
  • Full-text: 0