Pyrin domain

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1pn5 , 1ucp , 2hm2

PAAD/DAPIN/Pyrin domain
PAAD/DAPIN/Pyrin domain
Identifiers
Symbol	PAAD_DAPIN
Pfam	PF02758
Pfam clan	CL0041
InterPro	IPR004020
PROSITE	PS50824
SCOP2	1pn5 / SCOPe / SUPFAM
CDD	cd08305
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	1pn5 , 1ucp , 2hm2

Last updated September 28, 2024

NMR structure of the NLRP7 pyrin domain rendered in UCSF Chimera. Mesh electrostatic potential map using Coulombic coloring is superimposed showing areas of positive residue charge in blue and negative in maroon. Circled is the distinct elongated a2-a3 loop that is characteristic of pyrin domains. 2KM6NLRP7NMR.png — NMR structure of the NLRP7 pyrin domain rendered in UCSF Chimera. Mesh electrostatic potential map using Coulombic coloring is superimposed showing areas of positive residue charge in blue and negative in maroon. Circled is the distinct elongated α2-α3 loop that is characteristic of pyrin domains.

(Left) Side view of the Cryo-EM structure of AIM2 PYD filaments showing homotypic PYD-PYD aggregation in inflammasome assembly. (Right) Top down view of same filaments with hydrophobic residues in cyan forming symmetry around the center. Both rendered in UCSF chimera. AIM2sidetopdown.png — **(Left)** Side view of the Cryo-EM structure of AIM2 PYD filaments showing homotypic PYD-PYD aggregation in inflammasome assembly. **(Right)** Top down view of same filaments with hydrophobic residues in cyan forming symmetry around the center. Both rendered in UCSF chimera.

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 originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever.^[4] The domain is encoded in 23 human proteins and at least 31 mouse genes.^[5]

Proteins containing a pyrin domain are frequently involved in programmed cell death processes including pyroptosis and apoptosis.^[6]^[7] 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.^[5]

Structure

Pyrin domains are a ~90 amino acid motif present only at the N-terminus of proteins. The core is made of highly conserved hydrophobic residues surrounded by five or six alpha helices with α1→2 linkages. The hydrophobic core allows self-oligomerization into punctate or speck filamentous formations.^[5] 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.^[5]

Function

Proteins containing PYDs function as cytosolic pattern recognition receptors (PRRs) that sense damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs).^[5] Homotypic interactions between PYDs in receptor and adaptor proteins trigger downstream inflammasome formation.^[4]

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.^[8] 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. Pro-caspase-1 and caspase-8 are activated through an induced proximity mechanism. Caspase activity controls multiple downstream pathways to trigger pyroptosis and secretion of pro-inflammatory cytokines.^[4]^[8]

Types

Types of proteins containing a PYD 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 receptors containing a pyrin domain (NRLPs) and AIM2-like receptors (ALRs).^[5]^[8]

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 at the N-terminus and a CARD at the C-terminus. PYD interactions between ASC leads to oligomerization forming puncta or "specks" that become visible microscopically.^[7]^[9] The CARD recruits pro-caspase-1 which undergoes proximity induced autocleavage to form the active caspase-1 which in turn triggers maturation of IL-1β and IL-18.^[10]

NLRPs

NOD-like receptors exist in an inactive form until a conformational change is induced by their ligand. Some NLRs such as NLRP1 and NLRP2 have a straightforward mechanism by which the receptor binds to a PAMP triggering its activation, oligomerization and PYD-PYD ASC recruitment.^[7]^[8] In contrast, NLRP3 (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 Ca²⁺, 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.^[8]

ALRs

Absent in melanoma 2-like (AIM2-like) receptors function as recognition of foreign double stranded DNA. Two ALRs with pyrin domains, AIM2 and IFI16, assemble inflammasomes; AIM2 in the cytosol and IFI16 moves between the nucleus and cytosol functioning as a nuclear pathogen sensor.^[11] Unlike NLRPs which function in cytosolic PAMP and DAMP recognition, ALRs mainly act within the nucleus oligomerizing along the DNA staircase.^[8]

POPs

Pyrin-only proteins are unlike other PYD-containing proteins which contain a PYD with one or more other domains. Different POPs have electrostatic and structural similarities to the specific PYD they regulate.^[5] 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.^[7] Since most inflammasomes are formed by aggregation due to PYD-PYD interactions, POPs instead bind to PYDs preventing polymerization and therefore regulating and/or resolving inflammation response.^[5]

PYD domain containing proteins
Type	Subtype	Name	Stimulation signals	Function	Associated Diseases [5]
Adaptor		ASC	PAMPs or DAMPs binding to NLRPs or ALRs^[4]	Apoptosis, caspase activation, forms “specks” [2]	N/A
Pattern Recognition Receptors (PRRs)	Nucleotide-binding Leucine-rich Repeating with a Pyrin Domain or NOD-like Receptors (NLRPs)	NLRP1	Bacterial toxins, intracellular ATP depletion, muramyl dipeptide ^[4]	Caspase-1 and, uniquely, caspase-5 recruitment and ASC complex assembly	Arthritis, dyskeratosis, Chron's disease, hyper-inflammation (1)
		NLRP2	Downstream cytokine inhibition in response to immune suppressive monoclonal antibodies anti-CD3 and anti-CD28 ^[8]	Inflammasome assembly	N/A
		NLRP3	Extracellular ATP, Crystalline & Particulate structures (silica, alum, asbestos, amyloid-beta)^[4]	Possible link to ROS and redox signaling [1]	Cryopyrin-associated periodic syndromes, familial cold autoinflammatory syndrome, Muckle–Wells syndrome
		NLRP4	Cytosolic bacterial flagellin (i.e. Salmonella typhimurium) Type II secretion system components (i.e. Escherichia coli)^[4]	Modulates type I IFN signaling (5)	Enterocolitis, macrophage activation syndrome (MAS)
		NLRP6	Inflammation inducing and imbalanced gut microflora^[4]	Maintenance of intestinal homeostasis ^[4]	Colitis, colitis induced tumorigenesis, non-alcoholic fatty liver disease^[4]
		NLRP7	S. aureus, L. monocytogenes, lysosomal damage, bacterial acylated lipoproteins^[4]	Both pro and anti-inflammatory responses^[4]	Downregulation of IL-1β and TNFα in lymphocytes and monocytes in human patients with NLRP7 mutations ^[4]
		NLRP10	S. flexneri, C. albicans^[4]	Interacts with nodosome signaling	Defective TF1 and TF7 immune response to autoimmune encephalomyelitis in mice^[4]
		NLRP12	Yersinia pestis ^[4]	Negative regulator for pro-inflammatory cytokines ^[7]	Impaired chemokine response causing defects in migration of dendritic cells and lymph drainage^[4]
		NLRP14	Not linked to inflammasome activation or ASC interaction^[4]	Elusive function, unique dimerization in crystal structure^[7]	N/A
	Hematopoietic Interferon-Inducing Nuclear Proteins with 200 Amino Acid Repeat (HIN-200)	AIM2	Cytosolic viral dsDNA or bacteria (i.e. papillomavirus, Mycobacterium tuberculosis) ^[7]	Inflammasome formation along the DNA staircase^[4]	Susceptibility to F. tularensis and cytomegalovirus in mice^[4]
		IFI16	Latent viral DNA in nucleus and cytoplasm^[4]	Induces IFN- β in cytoplasm and inflammasome activating PRR^[4]	Sjogren's syndrome, systemic lupus erythematosus^[4]
Other		pyrin	Rho-GTPase inactivation (i.e. B. pertussis (pertussis toxin), B. cenocepacia (nosocomial pneumonia), C. botulinum (botulism), C. difficile (colitis), H. somni (TEME in cattle), V. parahaeomolyticus (acute gastroenteritis), Y. Pestis (plague)^[4]	Controls ASC-mediated apoptosis^[7]	Familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D syndrome (HIDS)^[7]

Related Research Articles

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

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 and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis. Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).

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 the formation of larger protein complexes via direct interactions between individual CARDs. CARDs are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

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 various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

PYCARD, often referred to as ASC, is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome.

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. NLRP1 is expressed by a variety of cell types, which are predominantly epithelial or hematopoietic. The expression is also seen within glandular epithelial structures including the lining of the small intestine, stomach, airway epithelia and in hairless or glabrous skin. NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD. Its highest expression was detected in human skin, in psoriasis and in vitiligo. Polymorphisms of NLRP1 were found in lupus erythematosus and diabetes type 1. Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the protease in anthrax lethal factor.

NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.

NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the NLRP2 gene.

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.

NACHT, LRR and PYD domains-containing protein 4 is a protein that in humans is encoded by the NLRP4 gene.

Interferon-inducible protein AIM2 also known as absent in melanoma 2 or simply AIM2 is a protein that in humans is encoded by the AIM2 gene.

The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K⁺ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

References

↑ Bank, RCSB Protein Data. "RCSB PDB - 2KM6: NMR structure of the NLRP7 Pyrin domain". www.rcsb.org. Retrieved 2021-12-11.
1 2 "Supplemental Information 4: UCSF Chimera". doi: 10.7717/peerj.4593/supp-4 .{{cite journal}}: Cite journal requires |journal= (help)
↑ Bank, RCSB Protein Data. "RCSB PDB - 6MB2: Cryo-EM structure of the PYD filament of AIM2". www.rcsb.org. Retrieved 2021-12-11.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I (2019). "The Pyrin Inflammasome in Health and Disease". Frontiers in Immunology. 10: 1745. doi: 10.3389/fimmu.2019.01745 . PMC 6698799 . PMID 31456795.
1 2 3 4 5 6 7 8 Chu LH, Gangopadhyay A, Dorfleutner A, Stehlik C (February 2015). "An updated view on the structure and function of PYRIN domains". Apoptosis. 20 (2): 157–173. doi:10.1007/s10495-014-1065-1. PMC 4297229 . PMID 25451010.
↑ Bertin J, DiStefano PS (December 2000). "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". Cell Death and Differentiation. 7 (12): 1273–1274. doi: 10.1038/sj.cdd.4400774 . PMID 11270363.
1 2 3 4 5 6 7 8 9 Gumucio DL, Diaz A, Schaner P, Richards N, Babcock C, Schaller M, Cesena T (2002). "Fire and ICE: the role of pyrin domain-containing proteins in inflammation and apoptosis". Clinical and Experimental Rheumatology. 20 (4 Suppl 26): S45–S53. PMID 12371636.
1 2 3 4 5 6 7 Ratsimandresy RA, Dorfleutner A, Stehlik C (December 2013). "An Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology". Frontiers in Immunology. 4: 440. doi: 10.3389/fimmu.2013.00440 . PMC 3856626 . PMID 24367371.
↑ Vajjhala PR, Kaiser S, Smith SJ, Ong QR, Soh SL, Stacey KJ, Hill JM (August 2014). "Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly". The Journal of Biological Chemistry. 289 (34): 23504–23519. doi: 10.1074/jbc.M114.553305 . PMC 4156052 . PMID 25006247.
↑ Stehlik C (June 2007). "The PYRIN domain in signal transduction". Current Protein & Peptide Science. 8 (3): 293–310. doi:10.2174/138920307780831857. PMC 4259900 . PMID 17584123.
↑ Lu A, Li Y, Yin Q, Ruan J, Yu X, Egelman E, Wu H (2015-06-23). "Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2". Cell Discovery. 1 (1): 15013–. doi:10.1038/celldisc.2015.13. PMC 4646227 . PMID 26583071.

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[1] Bank, RCSB Protein Data. "RCSB PDB - 2KM6: NMR structure of the NLRP7 Pyrin domain". www.rcsb.org. Retrieved 2021-12-11.

[dx.doi.org-2] 1 2 "Supplemental Information 4: UCSF Chimera". doi: 10.7717/peerj.4593/supp-4 .{{cite journal}}: Cite journal requires |journal= (help)

[3] Bank, RCSB Protein Data. "RCSB PDB - 6MB2: Cryo-EM structure of the PYD filament of AIM2". www.rcsb.org. Retrieved 2021-12-11.

[Schnappauf_2019-4] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I (2019). "The Pyrin Inflammasome in Health and Disease". Frontiers in Immunology. 10: 1745. doi: 10.3389/fimmu.2019.01745 . PMC 6698799 . PMID 31456795.

[Chu_2015-5] 1 2 3 4 5 6 7 8 Chu LH, Gangopadhyay A, Dorfleutner A, Stehlik C (February 2015). "An updated view on the structure and function of PYRIN domains". Apoptosis. 20 (2): 157–173. doi:10.1007/s10495-014-1065-1. PMC 4297229 . PMID 25451010.

[pmid11270363-6] Bertin J, DiStefano PS (December 2000). "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". Cell Death and Differentiation. 7 (12): 1273–1274. doi: 10.1038/sj.cdd.4400774 . PMID 11270363.

[pmid12371636-7] 1 2 3 4 5 6 7 8 9 Gumucio DL, Diaz A, Schaner P, Richards N, Babcock C, Schaller M, Cesena T (2002). "Fire and ICE: the role of pyrin domain-containing proteins in inflammation and apoptosis". Clinical and Experimental Rheumatology. 20 (4 Suppl 26): S45–S53. PMID 12371636.

[Ratsimandresy_2013-8] 1 2 3 4 5 6 7 Ratsimandresy RA, Dorfleutner A, Stehlik C (December 2013). "An Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology". Frontiers in Immunology. 4: 440. doi: 10.3389/fimmu.2013.00440 . PMC 3856626 . PMID 24367371.

[9] Vajjhala PR, Kaiser S, Smith SJ, Ong QR, Soh SL, Stacey KJ, Hill JM (August 2014). "Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly". The Journal of Biological Chemistry. 289 (34): 23504–23519. doi: 10.1074/jbc.M114.553305 . PMC 4156052 . PMID 25006247.

[10] Stehlik C (June 2007). "The PYRIN domain in signal transduction". Current Protein & Peptide Science. 8 (3): 293–310. doi:10.2174/138920307780831857. PMC 4259900 . PMID 17584123.

[11] Lu A, Li Y, Yin Q, Ruan J, Yu X, Egelman E, Wu H (2015-06-23). "Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2". Cell Discovery. 1 (1): 15013–. doi:10.1038/celldisc.2015.13. PMC 4646227 . PMID 26583071.

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