Helical assembly in the death domain (DD) superfamily

Abstract

Death domain (DD) superfamily members play a central role in apoptotic and inflammatory signaling through formation of oligomeric molecular scaffolds. These scaffolds promote the activation of proinflammatory and apoptotic initiator caspases, as well as Ser/Thr kinases. Interactions between DDs are facilitated by a conserved set of interaction surfaces, type I, type II, and type III. Recently structural information on a ternary complex containing the DDs of MyD88, IRAK4, and IRAK2 and a binary complex containing Fas and FADD DDs has become available. This review will focus on how the three DD interaction surfaces cooperate to facilitate the assembly of these oligomeric signaling complexes.

Structure determination of helical filaments by solid-state NMR spectroscopy

“…S2), indicating that all protomers in the filament are in the same conformation and are arranged homogeneously in a symmetrical manner along the filament axis. This finding is consistent with known structures of oligomeric complexes in the death domain superfamily, all of which exhibit helical or pseudohelical symmetries, albeit with variable parameters and handedness (21).…”

“…Each protomer is in contact with six other protomers via three interfaces denoted Ia/Ib, IIa/ IIb, and IIIa,IIIb (Fig. 6 A-D), which are preserved in death domain complexes determined to date (2,21,36). The IIIa/IIIb interface mediates the intrastrand contacts that form the lefthanded 1-start helix.…”

“…The filaments are propagated in a prion-like manner and can be induced by the tandem CARDs of RIG-I-like receptors or by preformed MAVS CARD filaments (20). CARDs belong to the death domain superfamily of protein-protein interaction domains, which share a common six-helix bundle fold and form homo-and hetero-oligomeric structures with variable symmetry (21). The crystal structure of monomeric MAVS CARD fused to…”

Multiple Binding Sites on the Pyrin Domain of ASC Protein Allow Self-association and Interaction with NLRP3 Protein

“…Similarly, during assembly of the Myddosome, MyD88 is recruited by activated Toll-like receptors and upon oligomerization recruits IRAK4 (62). The ability of ASC to self-associate and interact with NLRP3 indicates that ASC self-association may promote clustering of downstream recruited procaspase-1 as observed in other complexes where components cluster to allow activation of the terminally recruited effector molecules (63). Thus our study identifies many similarities between the roles of the PYD and other death fold domains in the assembly and activation of oligomeric signaling complexes.…”

Cellular Caspases: New Targets for the Action of Pharmacological Agents

“…Extracellular regions of death receptors interact with ligand trimers (CD95L, TNF, Apo3L, Apo2L, etc. ), and the latter trimerize the death receptors (crosslink 3 molecules of the receptor) [19,20]. The thus activated receptor interacts with a corresponding intracellular adaptor(s).…”