User:Amy.argabright/Pyrin domain

Current Stub/Entry:
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. It is also known as a PYD or PAAD/DAPIN domain, and is distantly evolutionarily related to the Death domain family of protein domains.

Proteins containing a pyrin domain are frequently involved in biological processes called inflammation and apoptosis. Proteins that possess a pyrin domain include intracellular microbial sensors called NOD-like receptors, and proteins associated with their function, such as PYCARD and certain fish caspases.

Lead
The PYD domain is the 4th member of the death domain family (DDF). The domain motif is 90 amino acids long and is only present at the N-terminus of proteins. It has been linked to apoptosis, NF-κB, and type-1 interferon signaling but is predominantly known for its role in inflammasome assembly. It was originally discovered in the pyrin protein. The deletion of the MEFV gene is the cause of Mediterranean Familial Fever. Since then, the domain has been found in around 20 human proteins, a majority of which have roles in inflammation response to cytosolic pathogens.

Intro
Proteins containing PYD domains function as cytosolic pattern recognition receptors (PRRs) that sense danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), triggering downstream inflammasome formation [5].

Among these are an adaptor apoptosis-associated speck-like protein (ASC), regulatory proteins like pyrin and POPs (pyrin-only proteins), receptors such as NOD-like receptor proteins (NRLPs) and cryopyrin, and HIN-200 proteins like absent in melanoma 2 (AIM2) [4].

Most PYD domains form PYD-PYD homotypic interactions between two proteins containing it. Typically, receptor proteins (such as NLRs and ALRs) are activated by their putative DAMP or PAMP. Once activated, an adaptor protein (ASC) containing a PYD and a caspase recruitment domain (CARD) is recruited forming a PYD-PYD interaction with the receptor. Multiple ASCs oligomerize activating pro-caspases through an induced proximity mechanism forming an inflammasome [I’m adding more about PYD-PYD in inflammasomes… it’s complicated] [1]. Caspases can then cascade to multiple downstream apoptotic and pyroptotic pathways to degrade cellular components and recruit immune cells [5].

Structure
PYDs 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 six alpha helices with α1→2 linkage. Generally, polar residues on the surface of the domain allow homotypic PYD-PYD interactions. Acidic residues are 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 [1].

[Note: I am going to add a specific section for function once I find out how the recruitment of inflammasome elements works biochemically in relation to PYD-PYD interaction.]

[Below will be subsection describing the general role of proteins with PYD domains with links to their wikis if they exist and differences in their homotypic interaction domains.]

ASC
ASC is an adaptor protein and is part of apoptosis, pro-caspase 1 recruitment and activation, as well as NF-B 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. PYD-PYD homotypic interactions between ASC leads to oligomerization forming puncta or "specks" that become visible microscopically. The CARD domain recruits pro-caspase-1 and, since ASC is

oligomerized, pro-caspase-1 undergoes proximity induced autocleavage to form the active caspase-1 which in turn triggers maturation of pro-IL-1β and pro-IL18.

NLRPs
One of two inflammasome sensors- nucleotide-binding and oligomerization domain-like receptors with a pyrin domain.

ALRs
Absent in melanoma 2-like receptors function in double stranded DNA recognition. Two ALRs with pyrin domains, AIM2 and IFI16, assemble inflammasomes; AIM2 does so in the cytosol and IFI16 moves between the nucleus and cytosol functioning as a nuclear pathogen sensor [3].

POPs
Pyrin-only proteins only contain a single pyrin domain unlike other proteins which contain pyrin with one or more domains. Different POPs have electrostatic and structural similarities to the pyrin domains of specific receptors and proteins. Most are encoded near the same genes as the pyrin-containing proteins they inhibit and POP1 and POP2 [maybe check this] are postulated to have arisen by exon duplication [2]. Since most inflammasomes are activated by PYD-PYD homotypic interactions leading to aggregation or by ASC-PYD polymerizing leading to caspase activation. POPs instead bind to PYD domains preventing polymerization and therefore regulating PYD interactions.

HIN-200
Linked Inflammatory Disorders

References

[1] Chu, L. H.; Gangopadhyay, A.; Dorfleutner, A.; Stehlik, C. An Updated View on the Structure and Function of PYRIN Domains. Apoptosis 2015, 20 (2), 157–173. https://doi.org/10.1007/s10495-014-1065-1.

[2] Gumucio, D. L.; Diaz, A.; Schaner, P.; Richards, N.; Babcock, C.; Schaller, M.; Cesena, T. Fire and ICE: The Role of Pyrin Domain-Containing Proteins in Inflammation and Apoptosis. Clin Exp Rheumatol 2002, 20 (4 Suppl 26), S45-53.

[3] Lu, A.; Li, Y.; Yin, Q.; Ruan, J.; Yu, X.; Egelman, E.; Wu, H. Plasticity in PYD Assembly Revealed by Cryo-EM Structure of the PYD Filament of AIM2. Cell Discov 2015, 1 (1), 15013. https://doi.org/10.1038/celldisc.2015.13.

[4] Ratsimandresy, R. A.; Dorfleutner, A.; Stehlik, C. An Update on PYRIN Domain-Containing Pattern Recognition Receptors: From Immunity to Pathology. ''Front. Immunol. 2013, 4''. https://doi.org/10.3389/fimmu.2013.00440.

[5] Schnappauf, O.; Chae, J. J.; Kastner, D. L.; Aksentijevich, I. The Pyrin Inflammasome in Health and Disease''. Front. Immunol''. 2019, 10, 1745. https://doi.org/10.3389/fimmu.2019.01745.

[6] Stehlik, C. The PYRIN Domain in Signal Transduction. Curr Protein Pept Sci 2007, 8 (3), 293–310. https://doi.org/10.2174/138920307780831857

[7] Vajjhala, P. R.; Kaiser, S.; Smith, S. J.; Ong, Q.-R.; Soh, S. L.; Stacey, K. J.; Hill, J. M. Identification of Multifaceted Binding Modes for Pyrin and ASC Pyrin Domains Gives Insights into Pyrin Inflammasome Assembly. Journal of Biological Chemistry 2014, 289 (34), 23504–23519. https://doi.org/10.1074/jbc.M114.553305.