Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain
Publication Year 2022-10-26,Volume 298,Issue #12,Page 102645
Journal Title
Journal of Biological Chemistry
The inflammasome sensor NLRP1 detects a variety of pathogen-derived molecular patterns to induce an inflammatory immune response by triggering pyroptosis and cytokine release. A number of mutations and polymorphisms of NLRP1 are known to cause autoinflammatory diseases, the functional characterization of which contributes to a better understanding of NLRP1 regulation. Here, we assessed the effect of the common NLRP1 variant M1184V, associated with asthma, inflammatory bowel disease, and diabetes, on the protein level. Our size-exclusion chromatography experiments show that M1184V stabilizes the FIIND domain in a monomeric conformation. This effect is independent of autoproteolysis. Additionally, molecular dynamics simulations reveal that the methionine residue increases flexibility within the ZU5 domain, while valine decreases flexibility, potentially indirectly stabilizing the catalytic triad responsible for autocleavage. By keeping the FIIND domain monomeric, formation of a multimer of full-length NLRP1 is promoted. We found that the stabilizing effect of the valine further leads to improved DPP9 binding capacities for the FIIND domain as well as the full-length protein as determined by surface plasmon resonance. Moreover, our immunoprecipitation experiments confirmed increased DPP9 binding for the M1184V protein in cells, consistent with improved formation of an autoinhibited complex with DPP9 in activity assays. Collectively, our study establishes a molecular rationale for the dichotomous involvement of the NLRP1 variant M1184V in autoimmune syndromes.
Research Division(s)
Inflammation; Advanced Technology And Biology
PubMed ID
Open Access at Publisher's Site
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Creation Date: 2022-11-08 02:27:11
Last Modified: 2022-12-05 08:05:18
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