Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

Arakelov, Grigor; Arakelov, Vahram; Nazaryan, Karen

doi:10.1002/prot.25494

Cited by 8 publications

(7 citation statements)

References 34 publications

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“…The current global results of MM scores for interface residues (Ser744, Pro710, Ile703, Ala726, and Met671) of the B30.2/SPRY-casp1/p20 complex showed that mutant patterns of these residues could be classified as severity relevant variants. The severity impact for these variants is partially consistent with what obtained by Arakelov et al [ 27 ].…”

Section: Discussionsupporting

confidence: 91%

Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex

Fayez

Eldeen

Zarouk

et al. 2022

Journal of Genetic Engineering and Biotechnology

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Background The B30.2 variants lead to most relevant severity forms of familial Mediterranean fever (FMF) manifestations. The B30.2 domain plays a key role in protein-protein interaction (PPI) of pyrin with other apoptosis proteins and in regulation the cascade of inflammatory reactions. Pyrin-casp1 interaction is mainly responsible for the dysregulation of the inflammatory responses in FMF. Lower binding affinity was observed between the mutant B30.2 pyrin and casp1 without the release of the complete pathogenicity mechanism. The aim of this study was to identify the possible effects of the interface pocked residues in B30.2/SPRY-Casp1/p20 complex using molecular mechanics simulation and in silico analysis. Results It was found that Lys671Met, Ser703Ile, and Ala744Ser variants led mainly to shift of the binding affinity (∆G), dissociation constant (Kd), and root mean square deviation (RMSD) in B30.2/SPRY-Casp1/p20 complex leading to dynamic disequilibrium of the p20-B30.2/SPRY complex toward its complex form. The current pathogenicity model and its predicted implementation in the relevant colchicine dosage were delineated. Conclusion The molecular mechanics analysis of B30.2/SPRY-p20 complex harboring Lys671Met, Ser703Ile, and Ala744Ser variants showed dynamic disequilibrium of B30.2/SPRY-casp1/p20complex in context of the studied variants that could be a new computational model for FMF pathogenicity. This study also highlighted the specific biochemical markers that could be useful to adjust the colchicine dose in FMF patients.

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Section: Discussionsupporting

confidence: 91%

Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex

Fayez

Eldeen

Zarouk

et al. 2022

Journal of Genetic Engineering and Biotechnology

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“…The B30.2 domain has been shown to interact with caspase-1 leading to the hypothesis that the B30.2 domain could regulate pyrin inflammasome through caspase-1 inhibition [ 25 – 27 ]. Yet, the above results demonstrate that the B30.2 domain regulates pyrin activation upstream of ASC speck formation suggesting that it may act independently of caspase-1.…”

Section: Resultsmentioning

confidence: 99%

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

et al. 2023

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Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. In addition, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.

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“…The B30.2 domain has long been hypothesized to negatively regulate human pyrin. Yet, the proposed mechanisms are unclear and include interaction of the B30.2 with NLRP3 to mediate autophagy-mediated degradation 33 , with PKN1 to modulate pyrin phosphorylation 6 or with caspase-1 25,26 or IL-1β 34,35 to directly regulate these in ammasome mediators. Here, we clearly demonstrate that the B30.2 domain is dispensable for pyrin in ammasome response in response to TcdA.…”

Section: Discussionmentioning

confidence: 99%

“…These results thus indicate that the B30.2-mediated regulation takes place downstream of pyrin dephosphorylation but upstream of ASC speck formation. The B30.2 domain has been shown to interact with caspase-1 leading to the hypothesis that the B30.2 domain could regulate pyrin in ammasome through caspase-1 inhibition [25][26][27] . Yet, the above results demonstrate that the B30.2 domain regulates pyrin activation upstream of ASC speck formation suggesting that it may act independently of caspase-1.…”

Section: B302 Domain Is Dispensable For Pyrin Activation In Response ...mentioning

confidence: 99%

Mutations in the B30.2 and the Central Helical scaffold domains of pyrin differentially affect inflammasome activation

Chirita

Magnotti

Bronnec

et al. 2022

Preprint

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Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. Additionally, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.

show abstract

Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

Cited by 8 publications

References 34 publications

Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex

Dynamic disequilibrium-based pathogenicity model in mutated pyrin’s B30.2 domain—Casp1/p20 complex

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

Mutations in the B30.2 and the Central Helical scaffold domains of pyrin differentially affect inflammasome activation

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