title: 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 approximately 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.
authors.affiliation: Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA. fairbo@gene.com
authors.forename: W J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: N C
authors.initials: NC
authors.lastname: Gordon
authors.forename: E W
authors.initials: EW
authors.lastname: Humke
authors.forename: K M
authors.initials: KM
authors.lastname: O'Rourke
authors.forename: M A
authors.initials: MA
authors.lastname: Starovasnik
authors.forename: J P
authors.initials: JP
authors.lastname: Yin
authors.forename: V M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D002942:Circular Dichroism; D003598:Cytoskeletal Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D000071198:Pyrin; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D003598:Cytoskeletal Proteins; D011506:Proteins; D000071198:Pyrin