Leucine-rich repeats and death domain containing, also known as LRDD or p53-induced protein with a death domain (PIDD), is a protein which in humans is encoded by the LRDD gene.
The leucine-rich repeat (LRR), first identified by Patthy, is a domain involved in protein-protein interactions and is present in numerous proteins that serve a variety of cellular roles. Leucine-rich repeats (LRR) proteins in eukaryotic cells are found in the nucleus, cytoplasm, extracellular matrix and plasma membrane.
The identification of PIDD1 PIDD, now officially known as PIDD1 (p53-induced death domain protein 1), a transformation of name was necessary to avoid confusion with primary immune deficiency disorders, which are often abbreviated similarly in scientific literature. Notably, no PIDD1 orthologues have been identified in non-vertebrates, and PIDD1 paralogues have not been found in vertebrates. Initially, PIDD1 was also referred to as leucine-rich repeat and death domain containing protein (LRDD) and was independently reported by two research groups in 2000.Telliez, J.-B., Bean, K. M. and Lin, L.-L. (2000). LRDD, a novel leucine rich repeat and death domain containing protein. Biochim. Biophys. Acta 1478, 280-288. https://doi.org/10.1016/S0167-4838(00)00029-7Lin, Y., Ma, W. and Benchimol, S. (2000). Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat. Genet. 26, 124-127. https://doi.org/10.1038/79102
Death domain Telliez and colleagues, in a bioinformatics search for proteins possessing a death domain that resembles the one found in human receptor-interacting serine/threonine kinase 1 (RIPK1, also known as RIP1), discovered a protein and named it LRDD based on its structural characteristics.Telliez, J.-B., Bean, K. M. and Lin, L.-L. (2000). LRDD, a novel leucine rich repeat and death domain containing protein. Biochim. Biophys. Acta 1478, 280-288. https://doi.org/10.1016/S0167-4838(00)00029-7 Through sequence analysis, it was discovered to contain leucine-rich repeats (LRRs) at the N-terminal region, ZU5 domains (found in ZO-1 and Unc5-like netrin receptors) in the middle section, and a death domain (DD) at the C-terminus. Additionally, a structural domain referred to as the uncharacterized protein domain in UNC5, PIDD, and ankyrins (UPA) was also identified between the ZU5 domain and the death domain (DD).Wang, R., Wei, Z., Jin, H., Wu, H., Yu, C., Wen, W., Chan, L.-N., Wen, Z. and Zhang, M. (2009). Autoinhibition of UNC5b revealed by the cytoplasmic domain structure of the receptor. Mol. Cell 33, 692-703. https://doi.org/10.1016/j.molcel.2009.02.016
Differential display analysis Also, a differential display analysis conducted in an erythroleukaemia cell line by Lin and co-researchers discovered that PIDD1 is a direct transcriptional target of p53.Lin, Y., Ma, W. and Benchimol, S. (2000). Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat. Genet. 26, 124-127. https://doi.org/10.1038/79102 Furthermore, PIDD1 overexpression inhibited cell growth by triggering apoptosis in p53-deficient cells, an effect that was reversed when PIDD1 was knocked down. This led to the assumption that PIDD1 plays a critical role in the apoptotic pathway regulated by p53.Lin, Y., Ma, W. and Benchimol, S. (2000). Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat. Genet. 26, 124-127. https://doi.org/10.1038/79102 In p53-deficient HCT116 and HEK293 cells which express the large T antigen, a basal level of PIDD1 expression was observed. This finding suggests that PIDD1 may play roles beyond its traditional involvement in the p53-mediated DNA damage response.Cuenin, S., Tinel, A., Janssens, S. and Tschopp, J. (2008). p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress. Oncogene 27, 387-396. https://doi.org/10.1038/sj.onc.1210635inel, A., Janssens, S., Lippens, S., Cuenin, S., Logette, E., Jaccard, B., Quadroni, M. and Tschopp, J. (2007). Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway. EMBO J. 26, 197-208. https://doi.org/10.1038/sj.emboj.7601473
Structure of PIDD1
Death fold Proteins with a death domain (DD), such as PIDD1, are defined by a structural framework consisting of six α-helical bundles, referred to as a 'death fold'.
This structure is also present in other proteins that contain domains like the caspase recruitment domain (CARD), death effector domain (DED), pyrin domain (PYD), or combinations of these motifs (e.g., DD/CARD, DD/DED, PYRIN/CARD). These death folds facilitate homotypic protein-protein interactions (such as DD/DD or CARD/CARD), enabling the formation of large multi-protein signaling complexes. Notable examples include the apoptosome, which contains apoptotic protease-activating factor 1 (APAF1) and caspase-9, and the death-inducing signaling complex (DISC) associated with caspase-8 and members of the tumor necrosis factor receptor (TNFR) superfamily.Langlais, C., M. A. Hughes, K. Cain, and MacFarlane, M. (2015). Biochemical analysis of initiator caspase-activating complexes: the apoptosome and the death-inducing signaling complex. Cold Spring Harb. Protoc. 2015, pdb top070326. https://doi.org/10.1101/pdb.top070326
Parts and cleavages Transcript variant 1 of PIDD1 mRNA in humans, produces a full-length PIDD1 protein consisting of 910 amino acids, with a molecular weight of about 100 kDa. This protein can be broken down into three parts: a 48 kDa N-terminal fragment called PIDD-N, and two C-terminal fragments, PIDD-C (51 kDa) and PIDD-CC (37 kDa). These cleavages occur at positions S446 and S588 through an autoproteolytic process that resembles proteins like inteins or nucleoporin Nup98 undergo self-cleavage.Hodel, A. E., Hodel, M. R., Griffis, E. R., Hennig, K. A., Ratner, G. A., Xu, S. and Powers, M. A. (2002). The three-dimensional structure of the autoproteolytic, nuclear pore-targeting domain of the human nucleoporin Nup98. Mol. Cell 10, 347-358. https://doi.org/10.1016/S1097-2765(02)00589-0 These proteins contain a conserved HSF tripeptide framework that enables a hydrophilic attack of the hydroxyl-group within the serine residue on the preceding peptide bond, converting it into an ester bond that is susceptible to cleavage by an additional nucleophile.Hodel, A. E., Hodel, M. R., Griffis, E. R., Hennig, K. A., Ratner, G. A., Xu, S. and Powers, M. A. (2002). The three-dimensional structure of the autoproteolytic, nuclear pore-targeting domain of the human nucleoporin Nup98. Mol. Cell 10, 347-358. https://doi.org/10.1016/S1097-2765(02)00589-0Mills, K. V., Johnson, M. A. and Perler, F. B. (2014). Protein splicing: how inteins escape from precursor proteins. J. Biol. Chem. 289, 14498-14505. https://doi.org/10.1074/jbc.R113.540310Tinel, A., Janssens, S., Lippens, S., Cuenin, S., Logette, E., Jaccard, B., Quadroni, M. and Tschopp, J. (2007). Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway. EMBO J. 26, 197-208. https://doi.org/10.1038/sj.emboj.7601473
The cleavage of full-length PIDD1 (FL-PIDD1) into PIDD-C or PIDD-CC seems to occur constitutively, meaning it happens regularly, which makes FL-PIDD1 levels remain low even when p53 is activated. However, the observation that PIDD-C accumulates before PIDD-CC in response to DNA damage supports the idea that PIDD-C is the primary form generated from FL-PIDD1.Tinel, A. and Tschopp, J. (2004). The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304, 843-846.Tinel, A., Janssens, S., Lippens, S., Cuenin, S., Logette, E., Jaccard, B., Quadroni, M. and Tschopp, J. (2007). Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway. EMBO J. 26, 197-208. https://doi.org/10.1038/sj.requires the interaction of the heat shock protein 90 (Hsp90) and its co-chaperone p23, which collaboemboj.7601473
Role of chaperones The autoprocessing of PIDD1 rate to induce the precise conformational state necessary for efficient self-cleavage. Hsp90 directly associates with full-length PIDD1 (FL-PIDD1), subsequently recruiting p23 to facilitate the stabilization and folding of PIDD1 into its active configuration.Weaver, A.J., Sullivan, W.P., Felts, S.J., Owen, B.A. and Toft, D.O. (2000). Crystal structure and activity of human p23, a heat shock protein 90 co-chaperone. J. Biol. Chem. 275, 23045-23052. http://www.jbc.org/content/275/30/23045.full Hsp70, another key chaperone, binds not only to full-length PIDD1 (FL-PIDD1) but also to its cleavage fragments, PIDD-N and PIDD-C, although the specific role of this interaction is not yet fully understood. In addition to facilitating autoprocessing, Hsp90 plays a crucial role in maintaining PIDD1's stability and function, highlighting the importance of chaperones in controlling both PIDD1 self-cleavage and its overall protein levels. When Hsp90 is inhibited, PIDD1 undergoes rapid degradation through the E3 ubiquitin-protein ligase CHIP (also called STUB1), which appears to favor the ubiquitination of PIDD-C over PIDD-CC. CHIP directly interacts with both PIDD1 and Hsp70, suggesting that Hsp70 may also be involved in regulating PIDD1. Although the PIDDosome can form in vitro after temperature changes, and the dissociation of Hsp90 is required for this process, Hsp90s initial interaction is critical for PIDD1’s function. Interruption of the Hsp90-PIDD1 complex disrupts PIDD1 autoprocessing and its interactions with effector proteins.Tinel, A., Eckert, M. J., Logette, E., Lippens, S., Janssens, S., Jaccard, B., Quadroni, M. and Tschopp, J. (2011). Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90. Cell Death Differ. 18, 506-515. https://doi.org/10.1038/cdd.2010.124
Multiprotein Complexes Containing PIDD1
PIDDosome PIDD-CC serves as a nucleating agent for the assembly of a complex with the dual adaptor protein RAIDD, which plays a pivotal role in the recruitment and activation of CASP2, potentially triggering apoptotic pathways. This assembly is widely recognized as the PIDDosome. In contrast, signaling pathways involving PIDD-C are primarily linked to the activation of NF-κB, thereby enhancing cell survival. In response to DNA damage, PIDD-C undergoes translocation to the nucleus, where it forms a complex with RIP1 and the NF-κB essential modulator (NEMO, also known as IKBKG), collectively termed the NEMO-PIDDosome.Janssens, S., Tinel, A., Lippens, S. and Tschopp, J. (2005). PIDD mediates NF-kappaB activation in response to DNA damage. Cell 123, 1079-1092. https://doi.org/10.1016/j.cell.2005.09.036 The term "PIDDosome" is commonly used to refer to a multiprotein complex that is made up of p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD), and the inactive precursor of the caspase family endopeptidase, called caspase-2.
Caps-2-PIDDosome Another important interaction is between Caspase-2 enzyme and PIDD1 to form Caps-2-PIDDosome. The formation of the Caspase–2–PIDDosome relies on the interaction with the adaptor protein RAIDD, which is characterized by the presence of a death domain (DD) and a caspase recruitment domain (CARD).Duan, H. and Dixit, V. M. (1997). RAIDD is a new ‘death’ adaptor molecule. Nature 385, 86-89. https://doi.org/10.1038/385086a0