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A pyrin domain (PYD, also known as PAAD/DAPIN) is a
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
and a subclass of
protein motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...
known as the
death fold
The death fold is a tertiary structure motif commonly found in proteins involved in apoptosis or inflammation-related processes. This motif is commonly found in domains that participate in protein–protein interactions leading to the format ...
, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by
MEFV
''MEFV'' (Mediterranean fever) is a human gene that provides instructions for making a protein called pyrin (also known as marenostrin). Pyrin is produced in certain white blood cells (neutrophils, eosinophils and monocytes) that play a role in in ...
. The mutation of the MEFV gene is the cause of the disease known as
Familial Mediterranean Fever
Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are sus ...
.
The domain is encoded in 23 human proteins and at least 31 mouse genes.
Proteins containing a pyrin domain are frequently involved in programmed cell death processes including
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
and
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
Proteins that possess a pyrin domain interact with the pyrin domains in other proteins to form of multi-protein complexes called inflammasomes and to trigger downstream immune responses.
Structure
Pyrin domains are a ~90 amino acid
motif present only at the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
of proteins. The core is made of highly conserved
hydrophobic residues
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
surrounded by five or six alpha helices with α1→2 linkages. The hydrophobic core allows self-oligomerization into punctate or speck filamentous formations.
Polar residues on the surface of the domain allow the formation of the characteristic homotypic PYD-PYD interactions. Acidic residues are typically located in the α2 and α3 helices while basic residues are located on the α1 and α4 helices. Compared to other members of the DDF they contain a distinctly elongated α2-α3 loop. This loop, especially α3, is highly variable among PYDs of different proteins which allows
binding specificity with other PYDs of the same type.
Function
Proteins containing PYD domains function as cytosolic pattern recognition receptors (PRRs) that sense danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs).
Homotypic interactions between PYD domains in receptor and adaptor proteins trigger downstream inflammasome formation.
First, receptor proteins (such as NLRs and ALRs) are activated by their putative DAMP or PAMP ligand. These receptors undergo a conformational change exposing their PYD domain.
Generally, an adaptor protein (ASC) containing both a PYD and a caspase recruitment domain (CARD) is recruited forming a PYD-PYD electrostatic interaction with the receptor's domain. More ASC-PYDs spontaneously self-oligomerize and forming a multi-protein complex called an
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
. Pro-
caspase-1
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolysis, proteolytically cleaves other proteins, such as the Protein precursor, precursors of the inflammatory cytokines Interleukin 1 beta, interleuki ...
and
caspase-8
Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3.
''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also presen ...
are activated through an induced proximity mechanism. Caspases can then cascade to multiple downstream pathways to trigger
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
and secretion of pro-inflammatory cytokines.
Types
Types of proteins containing a PYD domain include an adaptor,
apoptosis-associated speck-like protein containing a CARD (ASC), regulatory proteins like pyrin or pyrin-only proteins (POPs), receptors such as
NOD-like receptor
The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs) (also known as nucleotide-binding leucine-rich repeat receptors), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the ...
s containing a pyrin domain (NRLPs) and
AIM2-like receptors (ALRs).
ASC
ASC is an adaptor protein and is part of apoptosis, pro-caspase 1 recruitment and activation, as well as NF-κB transcription factor activation. ASC contains only two domains: the PYD domain at the N-terminus and a CARD (caspase recruitment domain) at the C-terminus. Pyrin domain interactions between ASC leads to oligomerization forming puncta or "specks" that become visible microscopically.
The
CARD 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 ...
recruits pro-caspase-1 which undergoes proximity induced autocleavage to form the active
caspase-1
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolysis, proteolytically cleaves other proteins, such as the Protein precursor, precursors of the inflammatory cytokines Interleukin 1 beta, interleuki ...
which in turn triggers maturation of
IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
and
IL-18.
NLRPs
NOD-like receptors exist in an inactive form until a conformational change is induced by their ligand. Some NLRs such as
NLRP1
NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. Material was copied from this source, which is available under Creative Commons Attribution 4. ...
and
NLRP2
NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the ''NLRP2'' gene.
NALP proteins, such as NALP2, are characterized by an N-terminal pyrin domain (PYD) and are involved in the activation of caspase-1 (C ...
have a straightforward mechanism by which the receptor binds to a PAMP triggering its activation, oligomerization and PYD-PYD ASC recruitment.
In contrast,
NLRP3
NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1.
NLRP3 is ...
(also known as cryopyrin) is the most well-studied NLR with a pyrin domain and has several diverse agonists. Proposed methods of its activation are more nuanced with intermediate effectors instead of a direct ligand-receptor interaction. An efflux of ATP due to tissue damage leading to an increase in Ca
2+, mitochondrial reactive oxygen species production due to cellular stress and lysosomal rupture releasing excess H
+ have all been proposed to inhibit different cofactors that normally inactivate NLRP3.
ALRs
Absent in melanoma 2-like receptors function as recognition of foreign double stranded DNA. Two ALRs with pyrin domains, AIM2 and
IFI16
Gamma-interferon-inducible protein Ifi-16 (Ifi-16) also known as interferon-inducible myeloid differentiation transcriptional activator is a protein that in humans is encoded by the ''IFI16'' gene.
Function
This gene encodes a member of the HI ...
, assemble inflammasomes; AIM2 in the cytosol and IFI16 moves between the nucleus and cytosol functioning as a nuclear pathogen sensor.
Unlike NLRPs which function in cytosolic PAMP and DAMP recognition, ALRs mainly act within the nucleus oligomerizing along the DNA staircase.
POPs
Pyrin-only proteins are unlike other PYD-containing proteins which contain a pyrin domain with one or more other domains. Different POPs have electrostatic and structural similarities to the specific pyrin domains they regulate.
Most are encoded near the same genes as the pyrin-containing proteins they inhibit; POP1 and POP2 are postulated to have arisen by exon duplication.
Since most inflammasomes are formed by aggregation due to PYD-PYD interactions, POPs instead bind to PYD domains preventing polymerization and therefore regulating and/or resolving inflammation response.
References
{{commons category, Pyrin domain, PYD
Protein domains