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

[familial mediterranean fever]

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 , R 42 W and A 89 T , on structural and functional properties of pyrin PYD were investigated . The R 42 W mutation had a significant effect on structure and increased stability . Although the R 42 W 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 .

Diseases
Validation

Diseases presenting "fever-associated" symptom

familial mediterranean fever

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