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as soon as is submitted to ZB.
Geometry-dependent interfaces shape NLRP3 pyrin domain assembly.
Int. J. Biol. Macromol. 375:153422 (2026)
NLRP3 inflammasome activation requires precise regulation of pyrin domain (PYD)-mediated protein-protein interactions to prevent spontaneous self-association while enabling rapid ASC adaptor recruitment. However, how local PYD interfaces encode the balance between restrained and assembly-competent states remains unclear. Here, we combine structural analysis, atomistic molecular dynamics simulations, targeted mutagenesis, heterotypic native/mutant split-luciferase complementation, ASC recruitment assays, microscale thermophoresis, and mass photometry to define geometry-dependent regulation of NLRP3 PYD self-association. A key feature of this work is the use of heterotypic native/mutant PYD pairings, enabling systematic comparison of interfacial, peripheral, and dual mutations and revealing interaction modes not accessible in homogeneous wild-type or mutant systems. We identify two distinct PYD-PYD geometries: a Type A-like restrained, non-filamentous dimeric contact and a Type B-like filament-compatible geometry that preserves the canonical Ia-Ib interface observed in active inflammasome assemblies. Both retain the six-helix PYD fold, indicating that functional differences arise primarily from interfacial organization rather than global structural changes. Residue-level perturbations further show that regulatory and CAPS-associated mutations remodel PYD assembly through distinct mechanisms. The S5D phosphomimetic substitution exhibits position- and orientation-dependent effects, being tolerated in permissive contexts but disrupting filament-compatible organization in sensitive interfaces. D31V decouples adaptor docking from higher-order assembly, whereas D21H reshapes restrained Type A-like interactions while preserving assembly competence. Together, these findings establish NLRP3 PYD self-association as a geometry-dependent process governed by electrostatic, hydrogen-bonding, and hydrophobic networks. This framework provides structural insight into regulatory modifications and CAPS-associated mutations and highlights PYD interfaces as potential targets for structure-guided modulation of NLRP3 inflammasome signaling.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Caps-associated Mutations ; Homotypic Pyd Assembly ; Interfacial Geometry ; Molecular Dynamics Simulations ; Nlrp3 Inflammasome ; Protein–protein Interactions ; Pyrin Domain (pyd) ; Structure-guided Modulation
ISSN (print) / ISBN
0141-8130
e-ISSN
1879-0003
Quellenangaben
Volume: 375,
Article Number: 153422
Publisher
Elsevier
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)