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FOR THE RECORD

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

¹ Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA
² Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA
³ Department of Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

Reprint requests to: Wayne J. Fairbrother, Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; e-mail: fairbo{at}gene.com; fax: 650-225-3734.

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.

Keywords: Apoptosis; caspase recruitment domain; death domain; fold recognition; inflammation; pyrin domain; protein modeling; secondary structure prediction

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