The
mucosa-associated lymphoid tissue lymphoma translocation 1 (
MALT1) paracaspase, a key component of the Carma1/Bcl10/MALT1 signalosome, is critical for NF-κB signaling in multiple contexts. MALT1 is thought to function as a scaffold and
protease to promote signaling; however, the biochemical and structural basis of
paracaspase action remains largely unknown. Here we report the 1.75-Å resolution crystal structure of the
MALT1 paracaspase region, which contains the
paracaspase domain and an ensuing Ig-like domain. The
paracaspase and the Ig domains appear as a single folding unit and interact with each other through extensive van der Waals contacts and hydrogen bonds. The
paracaspase domain adopts a fold that is nearly identical to that of classic
caspases and homodimerizes similarly to form an active
protease. Unlike
caspases, the active and mature form of the
paracaspase domain remains a single uncleaved
polypeptide and specifically recognizes the bound
peptide inhibitor Val-
Arg-Pro-Arg. In particular, the carboxyl-terminal
amino acid Arg of the inhibitor is coordinated by three highly conserved acidic residues. This structure serves as an important framework for deciphering the function and mechanism of paracaspases exemplified by MALT1.