Structures, Domains and Functions in Cell Death (DD, DED, CARD, PYD)


The death domain (DD), death effector domain (DED), caspase‐recruitment domain (CARD) and pyrin domain (PYD) are subfamilies of the DD superfamily. By mediating homotypic interactions, these proteins play important roles in the assembly and activation of apoptotic signalling complexes. They are responsible for caspase recruitment and for formation of oligomeric platforms for signalling. DD superfamily proteins have a common six‐helical bundle fold and show different surface features for each of the subfamilies. Most interestingly, the homotypic interactions within each subfamily are mostly mediated by asymmetric contacts, in which different surfaces of the interaction partners are adjacent to each other. The DD superfamily proteins appear to use three common types of asymmetric interactions to assemble into large oligomeric complexes.

Key concepts

  • Death domains (DDs), death effector domains (DEDs), caspase‐recruitment domains (CARDs) and pyrin domains (PYDs) are protein:protein interaction modules for formation of caspase‐activating complexes.

  • DDs, DEDs, CARDs and PYDs share a common six‐helical bundle fold.

  • Interactions within these domains are mostly asymmetric and conserved.

Keywords: death domain (DD); death effector domain (DED); tandem DED; caspase recruitment domain (CARD); pyrin domain (PYD); structure

Figure 1.

Domain organizations of selective proteins containing the DD superfamily domains. Abbreviations: CARD, caspase recruitment domain; CRD, cysteine‐rich domain; DD, death domain; DED, death effector domain; GUK, guanylate kinase‐like; LRR, leucine‐rich repeat; NOD, nucleotide‐binding oligomerization domain; PYD, pyrin domain; TIR, toll/interleukin 1 receptor and TM, transmembrane domain.

Figure 2.

Ribbon diagrams for each subfamily of the DD superfamily: (a) Fas DD, (b) FADDDED, (c) Apaf‐1CARD and (d) NLRP1 PYD. (e) Electrostatic surface representation of Apaf‐1CARD. (f) Stick model for the hydrogen‐bonding interactions in the charge triad of MC159 DED1. (g) Electrostatic surface representation of MC159 DED1 and DED2, showing the dumbbell‐shaped structure, the rich charges on one face and the location of the hydrophobic patch. Panels (f) and (g) are taken from Yang et al..

Figure 3.

Structural features of interactions in the DD superfamily. (a) Pelle DD:Tube DD complex, as a type II interaction. (b) Apaf‐1 CARD:procaspase‐9 CARD complex, as a type I interaction. (c) MC159 DED1:DED2 interaction, as a type I interaction. (d) Overview of the PIDD DD:RAIDD DD complex in two orthogonal orientations. (e) Superposition of the eight unique interactions in the PIDD DD:RAIDD DD complex. R:RAIDD DD; P:PIDDDD. There are three type I interactions, two type II interactions and three type III interactions. (f) Tetrameric Fas DD:FADDDD complex. Panels (d) and (e) are taken from Park et al..



Berube C, Boucher LM, Ma W et al. (2005) Apoptosis caused by p53‐induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proceedings of the National Academy of Sciences of the USA 102: 14314–14320.

Burckstummer T, Baumann C, Bluml S et al. (2009) An orthogonal proteomic‐genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunology 10: 266–272.

Chinnaiyan AM, O'Rourke K, Tewari M and Dixit VM (1995) FADD, a novel death domain‐containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81: 505–512.

Duan H and Dixit VM (1997) RAIDD is a new ‘death’ adaptor molecule. Nature 385: 86–89.

Eberstadt M, Huang B, Chen Z et al. (1998) NMR structure and mutagenesis of the FADD (Mort1) death‐effector domain. Nature 392: 941–945.

Fernandes‐Alnemri T, Yu JW, Datta P, Wu J and Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458: 509–513.

Franchi L, Eigenbrod T, Munoz‐Planillo R and Nunez G (2009) The inflammasome: a caspase‐1‐activation platform that regulates immune responses and disease pathogenesis. Nature Immunology 10: 241–247.

Hiller S, Kohl A, Fiorito F et al. (2003) NMR structure of the apoptosis‐ and inflammation‐related NALP1 pyrin domain. Structure 11: 1199–1205.

Hornung V, Ablasser A, Charrel‐Dennis M et al. (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase‐1‐activating inflammasome with ASC. Nature 458: 514–518.

Huang B, Eberstadt M, Olejniczak ET, Meadows RP and Fesik SW (1996) NMR structure and mutagenesis of the Fas (APO‐1/CD95) death domain. Nature 384: 638–641.

Kischkel FC, Hellbardt S, Behrmann I et al. (1995) Cytotoxicity‐dependent APO‐1 (Fas/CD95)‐associated proteins form a death‐inducing signaling complex (DISC) with the receptor. EMBO Journal 14: 5579–5588.

Lassus P, Opitz‐Araya X and Lazebnik Y (2002) Requirement for caspase‐2 in stress‐induced apoptosis before mitochondrial permeabilization. Science 297: 1352–1354.

Li FY, Jeffrey PD, Yu JW and Shi Y (2006) Crystal structure of a viral FLIP: insights into FLIP‐mediated inhibition of death receptor signaling. Journal of Biological Chemistry 281: 2960–2968.

Li P, Nijhawan D, Budihardjo I et al. (1997) Cytochrome c and dATP‐dependent formation of Apaf‐1/caspase‐9 complex initiates an apoptotic protease cascade. Cell 91: 479–489.

Liepinsh E, Barbals R, Dahl E et al. (2003) The death‐domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. Journal of Molecular Biology 332: 1155–1163.

Lin Y, Ma W and Benchimol S (2000) Pidd, a new death‐domain‐containing protein, is induced by p53 and promotes apoptosis. Nature Genetics 26: 122–127.

McEntyre JR and Gibson TJ (2004) Patterns and clusters within the PSM column in TiBS, 1992–2004. Trends in Biochemical Science 29: 627–633.

Natarajan A, Ghose R and Hill JM (2006) Structure and dynamics of ASC2, a pyrin domain‐only protein that regulates inflammatory signaling. Journal of Biological Chemistry 281: 31863–31875.

Park HH and Wu H (2006) Crystal structure of RAIDD death domain implicates potential mechanism of PIDDosome assembly. Journal of Molecular Biology 357: 358–364.

Park HH, Lo YC, Lin SC et al. (2007a) The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annual Review of Immunology 25: 561–586.

Park HH, Logette E, Rauser S et al. (2007b) Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128: 533–546.

Poppema S, Maggio E and van den Berg A (2004) Development of lymphoma in autoimmune lymphoproliferative syndrome (ALPS) and its relationship to Fas gene mutations. Leukemia & Lymphoma 45: 423–431.

Qin H, Srinivasula SM, Wu G et al. (1999) Structural basis of procaspase‐9 recruitment by the apoptotic protease‐activating factor 1. Nature 399: 549–557.

Rathmell JC and Thompson CB (2002) Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109(suppl.): S97–S107.

Reed JC, Doctor KS and Godzik A (2004) The domains of apoptosis: a genomics perspective. Science's STKE 2004: re9.

Riedl SJ and Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nature Reviews. Molecular Cell Biology 5: 897–907.

Riedl SJ, Li W, Chao Y, Schwarzenbacher R and Shi Y (2005) Structure of the apoptotic protease‐activating factor 1 bound to ADP. Nature 434: 926–933.

Rieux‐Laucat F, Fischer A and Deist FL (2003a) Cell‐death signaling and human disease. Current Opinion in Immunology 15: 325–331.

Rieux‐Laucat F, Le Deist F and Fischer A (2003b) Autoimmune lymphoproliferative syndromes: genetic defects of apoptosis pathways. Cell Death and Differentiation 10: 124–133.

Roberts TL, Idris A, Dunn JA et al. (2009) HIN‐200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323: 1057–1060.

Salvesen GS and Dixit VM (1999) Caspase activation: the induced‐proximity model. Proceedings of the National Academy of Sciences of the USA 96: 10964–10967.

Scott FL, Stec B, Pop C et al. (2009) The Fas‐FADD death domain complex structure unravels signalling by receptor clustering. Nature 457: 1019–1022.

Shisler JL and Moss B (2001) Molluscum contagiosum virus inhibitors of apoptosis: the MC159 v‐FLIP protein blocks Fas‐induced activation of procaspases and degradation of the related MC160 protein. Virology 282: 14–25.

Tartaglia LA, Ayres TM, Wong GH and Goeddel DV (1993) A novel domain within the 55 kd TNF receptor signals cell death. Cell 74: 845–853.

Thome M and Tschopp J (2001) Regulation of lymphocyte proliferation and death by FLIP. Nature Reviews. Immunology 1: 50–58.

Tinel A and Tschopp J (2004) The PIDDosome, a protein complex implicated in activation of caspase‐2 in response to genotoxic stress. Science 304: 843–846.

Wajant H (2002) The Fas signaling pathway: more than a paradigm. Science 296: 1635–1636.

Wang L, Miura M, Bergeron L, Zhu H and Yuan J (1994) Ich‐1, an Ice/ced‐3‐related gene, encodes both positive and negative regulators of programmed cell death. Cell 78: 739–750.

Xiao T, Towb P, Wasserman SA and Sprang SR (1999) Three‐dimensional structure of a complex between the death domains of Pelle and Tube. Cell 99: 545–555.

Yang JK, Wang L, Zheng L et al. (2005) Crystal structure of MC159 reveals molecular mechanism of DISC assembly and FLIP inhibition. Molecular Cell 20: 939–949.

Further Reading

Damiano JS and Reed JC (2004) CARD proteins as therapeutic targets in cancer. Current Drug Targets 5: 367–374.

Hong GS and Jung YK (2002) Caspase recruitment domain (CARD) as a bi‐functional switch of caspase regulation and NF‐kappaB signals. Journal of Biochemistry and Molecular Biology 35: 19–23.

Valmiki MG and Ramos JW (2009) Death effector domain‐containing proteins. Cell Mol Life Sci 66: 814–830.

Yu JW and Shi Y (2008) FLIP and the death effector domain family. Oncogene 27: 6216–6227.

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Wu, Hao, and Lo, Yu‐Chih(Dec 2009) Structures, Domains and Functions in Cell Death (DD, DED, CARD, PYD). In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021579]