The death domain superfamily comprises of the following subfamilies: the death domain, the death effector domain, the caspase recruitment domain, and the pyrin domain. CARD domains participate in the assembly of oligomeric signaling complexes by mediating homotypic interaction with other DD superfamily proteins. They are involved in apoptosis through their regulation of caspases that contain CARDs, including human caspases 1, 2, 8, 9 and 10, which could promote apoptosis through proteolytic degradation of other cellular components. CARDs are also involved in inflammation through their regulation of NF-kB activation in TNF signaling. The mechanisms by which CARDs activate caspases and NF-kB involve the assembly of oligomeric platforms, which can facilitate dimerization or serve as scaffolds on which proteases and kinases are assembled and activated. Although speculative, the complex may be stabilized by heterotypic interactions between the CARD and CARD-like domains of CARMA1, MALT1, and Bcl10. Clustering mechanisms of signaling molecules are the basis of adaptive and innate immune signal transduction. And these mechanisms are likely the molecular basis of how cIAP2-MALT1 fusion proteins activate the inflammatory pathway without ICG-001 847591-62-2 upstream activators. In order to better define the oligomerization potential of MALT1, we solved the structure of the MALT1 Nterminal CARD-like death domain and the tandem Ig-like domain. Here we show using structural biology that unlike the CARD-like death domain, the tandem Ig-like domains naturally form oligomers with a tendency towards dimers and tetramers. Structures reveal the molecular basis of dimerization and tetramerization by the Ig domain and suggest that MALT1 oligomerization may be mediated at least in part by its tandem Iglike domains. This study may help understand how MALT1 acts as an oligomeric scaffold protein to bind co-factors like Bcl10, CARMA1, and TRAF6, and activate the NF-kB pathway. The CARD domain is a protein-protein interaction module, typically associating with itself or other CARD-containing proteins, forming either dimers or trimers. In contrast to canonical CARD domains, the sixth helix in MALT1 is continuous with the fifth, forming a long helix that extends beyond the globular core of the domain. The unusual position of the sixth helix is also found in the crystal structures of another CARD containing protein, NOD1, where it is involved in a domain-swapping mechanism. The sixth helix sits in its canonical position, between helices A and E, but in another molecule.