Structural determinants of MALT1 protease activity

Abstract

The formation of the Carma1-BCL10-MALT1 complex is pivotal for T-cell receptor mediated activation of the transcription-factor NF-κB. Recently it was shown that in this complex MALT1 not only acts as a scaffolding protein but also possesses proteolytic activity mediated by its caspase-like domain. Here we show that, as described for caspases which play an essential role in apoptosis, proteolytic activity of MALT1 can be reconstituted by induced proximity. However, unlike caspases which cleave specifically C-terminal to an aspartate, MALT1 has an absolute specificity for arginine. We further determined the structure of the MALT1 domains responsible for proteolytic activity in the absence of ligand and in complex with a covalently bound substrate like inhibitor. The structures explain the specificity for cleavage after arginine, and show that the protease domain undergoes large conformational changes upon substrate binding that also affect the structure of the C-terminal Ig-like domain. This C-terminal Ig-like domain is required for MALT1 activity and likely important for the interaction of MALT1 with its binding partners