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Pathobiology and molecular basis of MALT lymphoma
Published in Franco Cavalli, Harald Stein, Emanuele Zucca, Extranodal Lymphomas, 2008
Francesco Bertoni, Randy D Gascoyne
The t(11;18)(q21;q21) translocation is the most common translocation, occurring in 15–40% of cases.3,7,12,14–18 It results in the reciprocal fusion of two genes, comprising the cellular inhibitor of apoptosis protein 2 (API2; official gene symbol is now BIRC3) on chromosome 11q21 with MALT1 on chromosome 18q21. The creation of a fusion protein encoded by API2/MALT1 on the derivative chromosome 11 is the key pathogenetic event. API2 belongs to the inhibitor of apoptosis proteins (IAP) family, characterized by the presence of one to three baculovirus IAP repeat (BIR) domains.19API2 contains three N-terminal BIR domains, a middle caspase recruitment domain (CARD), and a C-terminal zinc binding RING finger domain (Figure 8.2). MALT1, a paracaspase, is composed of an N-terminal Death Domain (DD), followed by two Ig-like C2 domains and a caspase-like domain. All the breakpoints in the API2 gene occur downstream of the third BIR domain but upstream of the C-terminal RING, with over 90% of them just proximal to the CARD domain. In contrast, the breakpoints involving the MALT1 gene are more variable, but always upstream of the caspase-like domain. Thus, the resulting fusion gene API2/MALT1 always includes the N-terminal region of API2 gene with three intact BIR domains and the C-terminal portion of the MALT1 gene containing an intact caspase-like domain. The specific selection of certain functional domains of API2 and MALT1 to form a fusion product strongly suggests the importance and synergy of these domains in oncogenic activities.20
A patent review of MALT1 inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Isabel Hamp, Thomas J. O’Neill, Oliver Plettenburg, Daniel Krappmann
Human mucosa-associated lymphoid tissue protein 1 (MALT1), also coined human paracaspase-I (HsPCA-I) [1], encodes a protease which was identified from the genomic translocation t(11;18)(q21;q21), a recurrent rearrangement in MALT lymphomas which leads to the generation of the oncogenic fusion protein API2-MALT1 [2]. Cellular MALT1 is a multi-domain protein comprising an N-terminal death domain (DD) and two immunoglobulin (Ig1/2) domains followed by the paracaspase (PCASP) and a C-terminal Ig3 domain (Figure 1). Sequence alignments revealed that the caspase-like fold of MALT1 is the only human homolog of an ancient family of paracaspases which display homology to metacaspases found in plants and fungi [3,4]. However, only in 2008 was it discovered that MALT1 is an active protease containing a histidine (H415) cysteine (C464) dyad in the active center and whose cleavage activity is induced in lymphocytes after antigen receptor engagement [5,6]. In contrast to caspases that cleave substrate proteins after aspartate, the MALT1 paracaspase strictly relies on the recognition of an arginine in the P1 substrate position, which at least partially explains the initial difficulties in demonstrating MALT1 protease activity [7,8]. Further, while caspase domains are sufficient to confer strong proteolytic activity, catalytic activity of the paracaspase domain requires the presence of the C-terminal Ig3 domain in MALT1 for stabilizing the active dimeric conformation [7,9]. Mono-ubiquitination in the intramolecular PCASP-Ig3 interface triggers protease activity in T cells, an activation process that is unique to MALT1 and not found in caspases [10,11]. Importantly, a pocket that forms between the paracaspase and Ig3 domains has been defined as the favored binding surface for highly selective MALT1 protease inhibitors, which target MALT1 by a noncompetitive, allosteric mode of action [12,13]. Thus, the unique features of MALT1 as the only human paracaspase have inspired the development of MALT1 inhibitors that are currently on or just beyond the rim of entering clinical evaluation.