Lorenzo Sborgi / Francesco Ravotti / Venkata P Dandey / Mathias S Dick / Adam Mazur / Sina Reckel / Mohamed Chami / Sebastian Scherer / Matthias Huber / Anja Böckmann / Edward H Egelman / Henning Stahlberg / Petr Broz / Beat H Meier / Sebastian Hiller /
PubMed 要旨
Inflammasomes are multiprotein complexes that control the innate immune response by activating caspase-1, thus promoting the secretion of cytokines in response to invading pathogens and endogenous ...Inflammasomes are multiprotein complexes that control the innate immune response by activating caspase-1, thus promoting the secretion of cytokines in response to invading pathogens and endogenous triggers. Assembly of inflammasomes is induced by activation of a receptor protein. Many inflammasome receptors require the adapter protein ASC [apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD)], which consists of two domains, the N-terminal pyrin domain (PYD) and the C-terminal CARD. Upon activation, ASC forms large oligomeric filaments, which facilitate procaspase-1 recruitment. Here, we characterize the structure and filament formation of mouse ASC in vitro at atomic resolution. Information from cryo-electron microscopy and solid-state NMR spectroscopy is combined in a single structure calculation to obtain the atomic-resolution structure of the ASC filament. Perturbations of NMR resonances upon filament formation monitor the specific binding interfaces of ASC-PYD association. Importantly, NMR experiments show the rigidity of the PYD forming the core of the filament as well as the high mobility of the CARD relative to this core. The findings are validated by structure-based mutagenesis experiments in cultured macrophages. The 3D structure of the mouse ASC-PYD filament is highly similar to the recently determined human ASC-PYD filament, suggesting evolutionary conservation of ASC-dependent inflammasome mechanisms.
EMDB-2971: Structure and assembly of the mouse ASC filament PDB-2n1f: Structure and assembly of the mouse ASC filament by combined NMR spectroscopy and cryo-electron microscopy 手法: EM (らせん対称) / 解像度: 4.0 Å
由来
mus musculus (ハツカネズミ)
キーワード
APOPTOSIS / mouse ASC filament / ASC Apoptosis-associated speck like protein containing a CARD / PYRIN domain / inflammasomes / death domain