The death fold is a tertiary structure motif commonly found in

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s involved in

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

-related processes. This motif is commonly found in domains that participate in protein–protein interactions leading to the formation of large functional complexes. Examples of death fold domains include the

death domain The death domain (DD) is a protein interaction module composed of a bundle of six alpha helix, alpha-helices. DD is a subclass of protein structural motif , motif known as the death fold and is related in sequence and structure to the death effecto ...

(DD),

death effector domain The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases (cysteine proteases) and proteins that regulate casp ...

(DED),

caspase recruitment domain Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate th ...

(CARD), and

pyrin domain A pyrin domain (PYD, also known as PAAD/DAPIN) is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was initially discovered in the pyri ...

(PYD). Death fold domains are an evolutionarily conserved superfamily of domains that mediate apoptotic signaling. The two types of

, extrinsic and intrinsic, are tightly regulated by the interplay of activating and inhibitory pathways. The interactions between the four different death fold motifs are a unifying mechanism in both types of apoptosis.

Structure

There is a large difference in the primary amino acid sequence of the four different death fold motifs, but each has a similar three-dimensional structure. Death-fold motifs are characterized by six to seven tightly coiled

alpha-helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

arranged in a "Greek-key" fold. The motifs permit specific interactions with proteins containing the correct homotypic death-fold domain.

Types

Caspase recruitment domain (CARD)

CARD-containing proteins are found throughout the animal kingdom. CARD domains are present on several mammalian

procaspases Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...

, and have functions in

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

processing, immune defense, and

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

activation. In insects and

nematodes The nematodes ( or ; ; ), roundworms or eelworms constitute the phylum Nematoda. Species in the phylum inhabit a broad range of environments. Most species are free-living, feeding on microorganisms, but many are parasitic. Parasitic worms (he ...

, CARDs so far seem restricted to apoptotic proteins.

Death domain (DD)

DDs are found primarily in

vertebrates Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

(although they are also present in some other animals). DDs are contained on cytokine receptors in the

TNF Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

receptor family. DD proteins function in apoptosis and NF-κB signaling in mammals, but only NF-κB signaling ''

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

''.

Death effector domain (DED)

DEDs are present on

caspases Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...

and are involved in caspase activation. DED-containing caspases function in death receptor-induced apoptosis in mammals, but differ in insects where they are involved in NF-κB signaling and antibacterial responses.

PYRIN

PYRINS are the most recently discovered death-fold domain, and their functions and interactions have yet to be clearly elucidated.

Binding and interactions

Death-fold motifs are believed to exert their effects solely through monovalent, homotypic interactions. In these interactions death-folds bind to another death-fold containing

domain A domain is a geographic area controlled by a single person or organization. Domain may also refer to: Law and human geography * Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...

through the same type of protein interaction domain. These interactions are highly specific, and there are no known interactions between different types of death-fold domains – in every known case the binding partners have homologous domain (DD-DD, CARD-CARD, DED-DED). The role of these homotypic interactions is thought to be self-assembly. This results in large multi-subunit structures made of only one type of protein.

References

* {{refend Cell biology Protein folds