Role of charged and hydrophobic residues in the oligomerization of the PYRIN domain of ASC

Mie Moriya, Shunichiro Taniguchi, Peter Wu, Edvards Liepinsh, Gottfried Otting, Junji Sagara*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    54 Citations (Scopus)

    Abstract

    Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein composed of two homophilic protein-protein interaction domains, a PYRIN domain (PYD) and a caspase recruitment domain. PYD-dependent oligomerization of ASC is thought to play a crucial role in formation of a molecular platform, the inflammasome, which activates caspase-1. When expressed in cells, the PYD of ASC was shown to form cytoplasmic filaments through self-association. Over 70 single point mutants were analyzed for filament formation in cells expressing the mutant proteins. The set of mutations comprised every single amino acid residue with a charged side chain (Arg, Lys, Asp, and Glu) and a large hydrophobic side chain (Ile, Leu, Met, Phe, Pro, and Val). Filament formation of the ASC PYD was prevented by mutation of Lys21, Leu25, Lys26, Pro40, Arg41, Asp48, and Asp51 of helices 2, 3, and 4. These data identify a coherent interaction surface, establishing a molecular model of PYD-PYD complexes with an important role for charge-charge interactions.

    Original languageEnglish
    Pages (from-to)575-583
    Number of pages9
    JournalBiochemistry
    Volume44
    Issue number2
    DOIs
    Publication statusPublished - 18 Jan 2005

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