Sborgi, Lorenzo and Ravotti, Francesco and Dandey, Venkata Prasad and Dick, Mathias S. and Mazur, Adam and Reckel, Sina and Chami, Mohamed and Scherer, Sebastian and Huber, Matthias and Böckmann, Anja and Egelman, Edward H. and Stahlberg, Henning and Broz, Petr and Meier, Beat H. and Hiller, Sebastian. (2015) Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy. Proceedings of the National Academy of Sciences of the United States of America, 112 (43). pp. 13237-13242.
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Abstract
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.
Faculties and Departments: | 05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Infection Biology (Broz) 05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Research IT (Podvinec) 05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller) 05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Structural Biology (Stahlberg) |
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UniBasel Contributors: | Mazur, Adam and Hiller Odermatt, Sebastian and Stahlberg, Henning and Broz, Petr and Podvinec, Michael |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | National Academy of Sciences |
ISSN: | 0027-8424 |
e-ISSN: | 1091-6490 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 21 Dec 2017 08:26 |
Deposited On: | 11 May 2016 08:40 |
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