The death fold is a tertiary structure motif commonly found in protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s involved in apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 or inflammation

Inflammation

Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

-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

Death domain

The death domain is a protein interaction module composed of a bundle of six alpha-helices. DD is a subclass of protein motif known as the death fold and is related in sequence and structure to the death effector domain and the caspase recruitment domain , which work in similar pathways and show...

 (DD), death effector domain

Death effector domain

The death-effector domain is a protein interaction domain found to regulate a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein...

 (DED), Caspase Recruitment Domain

CARD domain

Caspase recruitment domains, or Caspase activation and recruitment domains , are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct...

 (CARD), and pyrin domain

Pyrin domain

A pyrin domain is a protein domain and a subclass of protein motif known as the death fold; it allows a pyrin domain containing protein to interact with other proteins that contain a pyrin domain...

 (PYD).

Death fold domains are an evolutionarily conserved superfamily of domains that mediate apoptotic signaling. The two types of apoptosis, 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 arranged in a “Greek-key” fold. The motifs consist of several defined protein interactions with other suspected apoptotic roles (Lahm).

Four Death-Fold Domains

Caspase Recruitment Domain (CARD)
CARD-containing proteins are found throughout the animal kingdom and may also be present in fungi, plants, and prokaryotes. CARD domains are present on several mammalian procaspases, and have functions in apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 processing, immune defense, and NF-κB activation. In insects and nematodes, CARDs so far seem restricted to apoptotic proteins.

Death Domain (DD)
DDs are found primarily in vertebrates (although they are also present in some other animals). DDs are contained on cytokine receptors in the TNF

Tumor necrosis factors

Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...

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

Death Effector Domain (DED)
DEDs are present on caspases 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

Structural motif

In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...

 are believed to exert their effects solely through monovalent

Monovalent

Monovalent may refer to:*In chemistry, valence is a measure of the number of chemical bonds formed by the atoms of a given element. Monovalent is a synonym of univalent.*Monovalent ions contain one valence electron....

, homotypic interactions. In these interactions death-folds bind to another death-fold containing domain

Protein domain

A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...

 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 (Lahm). This results in large multi-subunit structures made of only one type of protein.