Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly

Vajjhala, Parimala R., Kaiser, Sebastian, Smith, Sarah J., Ong, Qi-Rui, Soh, Stephanie L., Stacey, Katryn J. and Hill, Justine M. (2014) Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly. Journal of Biological Chemistry, 289 34: 23504-23519. doi:10.1074/jbc.M114.553305

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Author Vajjhala, Parimala R.
Kaiser, Sebastian
Smith, Sarah J.
Ong, Qi-Rui
Soh, Stephanie L.
Stacey, Katryn J.
Hill, Justine M.
Title Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2014
Year available 2014
Sub-type Article (original research)
DOI 10.1074/jbc.M114.553305
Open Access Status File (Publisher version)
Volume 289
Issue 34
Start page 23504
End page 23519
Total pages 16
Place of publication Bethesda, MD United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2015
Language eng
Abstract Inflammasomes are macromolecular complexes that mediate inflammatory and cell death responses to pathogens and cellular stress signals. Dysregulated inflammasome activation is associated with autoinflammatory syndromes and several common diseases. During inflammasome assembly, oligomerized cytosolic pattern recognition receptors recruit procaspase-1 and procaspase- 8 via the adaptor protein ASC. Inflammasome assembly is mediated by pyrin domains (PYDs) and caspase recruitment domains, which are protein interaction domains of the death fold superfamily. However, the molecular details of their interactions are poorly understood. We have studied the interaction between ASC and pyrin PYDs that mediates ASC recruitment to the pyrin inflammasome, which is implicated in the pathogenesis of familial Mediterranean fever. We demonstrate that both the ASC and pyrin PYDs have multifaceted binding modes, involving three sites on pyrin PYD and two sites on ASC PYD. Molecular docking of pyrin-ASC PYD complexes showed that pyrin PYD can simultaneously interact with up to three ASC PYDs. Furthermore, ASC PYD can self-Associate and interact with pyrin, consistent with previous reports that pyrin promotes ASC clustering to form a proinflammatory complex. Finally, the effects of familial Mediterranean fever-Associated mutations, R42W and A89T, on structural and functional properties of pyrin PYD were investigated. The R42W mutation had a significant effect on structure and increased stability. Although the R42W mutant exhibited reduced interaction with ASC, it also bound less to the pyrin B-box domain responsible for autoinhibition and hence may be constitutively active. Our data give new insights into the binding modes of PYDs and inflammasome architecture.
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Institutional Status UQ
Additional Notes First Published on July 8, 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
Centre for Advanced Imaging Publications
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Citation counts: TR Web of Science Citation Count  Cited 9 times in Thomson Reuters Web of Science Article | Citations
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