Allosteric activation of MALT1.pdf (992.66 kB)
Download file

Allosteric activation of MALT1 by its ubiquitin-binding IG3 domain

Download (992.66 kB)
journal contribution
posted on 15.04.2020, 10:57 by Rebekka Schairer, Gareth Hall, Ming Zhang, Richard Cowan, Roberta Baravalle, Frederick Muskett, Peter Coombs, Chido Mpamhanga, Lisa Hale, Barbara Sixty, Justyna Iwaszkiewicz, Chantal Decaillet, Mai Perroud, Margot Thome, Mark Carr
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.

History

Citation

PNAS February 11, 2020 117 (6) 3093-3102

Author affiliation

Department of Molecular and Cell Biology

Version

AM (Accepted Manuscript)

Published in

Proceedings of the National Academy of Sciences of USA

Volume

117

Issue

6

Pagination

3093 - 3102

Publisher

National Academy of Sciences

issn

0027-8424

eissn

1091-6490

Acceptance date

30/12/2019

Copyright date

2020

Available date

24/01/2020

Publisher version

https://www.pnas.org/content/117/6/3093

Spatial coverage

United States

Language

En