The PYRIN domain: A member of the death domain‐fold superfamily

Abstract

PYRIN domains were identified recently as putative protein-protein interaction domains at the N-termini of several proteins thought to function in apoptotic and inflammatory signaling pathways. The ∼95 residue PYRIN domains have no statistically significant sequence homology to proteins with known three-dimensional structure. Using secondary structure prediction and potential-based fold recognition methods, however, the PYRIN domain is predicted to be a member of the six-helix bundle death domain-fold superfamily that includes death domains (DDs), death effector domains (DEDs), and caspase recruitment domains (CARDs). Members of the death domain-fold superfamily are well established mediators of protein-protein interactions found in many proteins involved in apoptosis and inflammation, indicating further that the PYRIN domains serve a similar function. An homology model of the PYRIN domain of CARD7/DEFCAP/ NAC/NALP1, a member of the Apaf-1/Ced-4 family of proteins, was constructed using the three-dimensional structures of the FADD and p75 neurotrophin receptor DDs, and of the Apaf-1 and caspase-9 CARDs, as templates. Validation of the model using a variety of computational techniques indicates that the fold prediction is consistent with the sequence. Comparison of a circular dichroism spectrum of the PYRIN domain of CARD7/DEFCAP/NAC/NALP1 with spectra of several proteins known to adopt the death domain-fold provides experimental support for the structure prediction.

The estrogen-responsive B box protein: a novel enhancer of interleukin-1β secretion

“…This secretion-promoting effect of EBBP for caspase-1 was much stronger after cotransfection of pro-and mature IL-1b expression plasmids (lanes 13-16, 21-24, supernatant). Highest secretion was observed after coexpression of the cytokine with either EBBP or individual EBBP domains (lanes [14][15][16][22][23][24]. Surprisingly, forced expression of EBBP and pro-and to a lesser extent mature IL-1b resulted in degradation of procaspase-1 (lanes 14, 15, 22, 23, lysate and supernatant).…”

“…12 The assembly of this complex relies only on homotypic interactions of the death domain fold family member caspase recruitment domain (CARD) and the recently identified pyrin domain. 11,13,14 The NALP1 protein contains an amino-terminal pyrin domain and a carboxyterminal CARD (Figure 2a). The latter allows binding to the CARD of procaspase-5, whereas the pyrin domain binds via the bipartite adaptor protein Asc, which consists only of a pyrin domain and a CARD, to the CARD of procaspase-1 ( Figure 2a).…”

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

“…10,11 It is composed of several identifiable conserved domains including an N-terminal PYD, which is a homotypic protein-protein interaction domain belonging to the six-helix bundle death domain (DD)-fold superfamily that includes DDs, death effector domains (DEDs), and caspaseassociated recruitment domains (CARDs). [12][13][14][15] The PYD is followed by two central B-box zinc-finger and coiled coil domains and a C-terminal B30.2/rfp/SPRY domain. Most FMF-associated mutations are localized in B30.2/rfp/SPRY domain, 16 suggesting that this domain is involved in the regulation of the activity of pyrin.…”

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

“…It appears that according to the cell type or to the spliced isoform studied, Pyrin can be localized diffusely or as specks, in the cytoplasm, but also in the nucleus. [15][16][17][18][19][20] Pyrin contains at the N-terminus a Pyrin domain (PYD), a member of the death effector-fold domains, [21][22][23] two B-boxes and a coiled-coil domain (BBCC), as well as a SPRY domain (also called B30.2 domain). The PYD found in Pyrin is also present in NALP proteins.…”