The death domain superfamily in intracellular signaling of apoptosis and inflammation

Abstract

The death domain (DD) superfamily comprising the death domain (DD) subfamily, the death effector domain (DED) subfamily, the caspase recruitment domain (CARD) subfamily, and the pyrin domain (PYD) subfamily is one of the largest domain superfamilies. By mediating homotypic interactions within each domain subfamily, these proteins play important roles in the assembly and activation of apoptotic and inflammatory complexes. In this chapter, we review the molecular complexes assembled by these proteins, the structural and biochemical features of these domains, and the molecular interactions mediated by them. By analyzing the potential molecular basis for the function of these domains, we hope to provide a comprehensive understanding of the function, structure, interaction, and evolution of this important family of domains.

Figure 1

Domain organizations of selective proteins containing the DD superfamily domains.

Figure 2

Ribbon diagrams for each subfamily of the DD superfamily, Fas DD (a), FADD DED (b), RAIDD CARD (c) and NALP1 PYD (d).

Figure 3

Structural features of DDs and DD: DD interactions. (a) A stereo diagram of the superimposed known DD structures. Green: RAIDD DD; Cyan: Fas DD; Red: FADD DD; Yellow: TNFR1 DD; Gray: p75 DD; Magenta: IRAK4 DD; Blue: Pelle DD; Orange: Tube DD. (b) Pelle DD: Tube DD complex. Pelle is shown in purple with segments for Tube interaction in magenta. Tube is shown in green with segments for Pelle interaction in red. (c) Hypothetical models for a three-fold symmetric Fas DD: FADD DD complex. In one model, FADD DD interacts with one Fas DD only. In the other model, FADD DD interacts with two adjacent Fas DD molecules.

Figure 4

Structural features of DEDs and tandem DEDs. (a) A ribbon diagram of the tandem DED structure of MC159. (b) A stereo diagram of superimposed known DED structures. Green: DED1 of MC159; Blue: DED2 of MC159; Pink: FADD DED and Yellow: PEA-15 DED. (c) Charge triad motif. (d) Surface features of MC159, showing the hydrophobic patch and charge triad surfaces that are conserved in almost all DEDs. (e) MC159 DED1: DED2 interaction. Panels c, d and e are modified from Yang et al. (116).

Figure 5

Structural features of CARDs and CARD: CARD interactions. (a) A stereo diagram of superimposed known CARD structures. Red: Apaf-1 CARD, Blue: ICEBERG CARD, Green: RAIDD CARD; Cyan: caspase-9 CARD; Violet: CED4 CARD. (b) Superimposed Apaf-1 CARD structures when determined alone (green), in complex with caspase-9 (violet) and in WD-deleted Apaf-1 (red). (c) Surface features of CARDs, showing the charged surfaces. Two orientations are shown, one similar to the caspase-9 interaction surface of Apaf-1 (left) and the other similar to the Apaf-1 interaction surface of caspase-9 (right). (d) Apaf-1 CARD: caspase-9 CARD structure. Apaf-1 CARD is shown in violet and caspase-9 CARD is in cyan.

Figure 6

Structural features of PYDs. (a) A stereo diagram of superimposed PYDs. Cyan: NALP1 PYD; Magenta: ASC PYD. (b) Electrostatic surface features of PYDs. Left: the two opposite sides of NALP1; Right: the two opposite sides of ASC.

Figure 7

Comparison of the three pairs of known interactions in the DD superfamily, the Pelle DD: Tube DD complex, the Apaf-1 CARD: caspase-9 CARD complex and the DED1: DED2 in the tandem DED MC159. DED1 of MC159 is superimposed respectively with Pelle DD in the complex (a), Tube DD in the complex (b), caspase-9 CARD in the complex (c) and Apaf-1 CARD in the complex (d). This figure was modified from Yang et al. (116).

Figure 8

Sequence and structural comparisons. (a) Phylogenetic tree of the DD superfamily constructed based on sequence similarity. Only those members with known structures are used. The calculation was performed using the multiple sequence alignment program MAFFT (http://timpani.genome.ad.jp/%7Emafft/server/). b) Phylogenetic tree of the DD superfamily constructed based on structural similarity. The calculation was performed using the program TraceSuite II (http://www-cryst.bioc.cam.ac.uk/~jiye/evoltrace/evoltrace.html).