2013
DOI: 10.1016/j.molcel.2013.08.032
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Structural Architecture of the CARMA1/Bcl10/MALT1 Signalosome: Nucleation-Induced Filamentous Assembly

Abstract: SUMMARY The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligo… Show more

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Cited by 163 publications
(231 citation statements)
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“…This observation suggests that the molecular mechanism of the ASCdependent innate immune response is conserved and follows the same biophysical principles in both species, implicating a biological role for the filament structure. Thereby, the helical arrangement and the interfaces I-III are in full agreement with other reported helical arrangements of death domains (17,43). The CARD in ASC-FL filaments was found to be dynamic and at least partially unfolded in our experimental conditions.…”
Section: Discussionsupporting
confidence: 91%
See 1 more Smart Citation
“…This observation suggests that the molecular mechanism of the ASCdependent innate immune response is conserved and follows the same biophysical principles in both species, implicating a biological role for the filament structure. Thereby, the helical arrangement and the interfaces I-III are in full agreement with other reported helical arrangements of death domains (17,43). The CARD in ASC-FL filaments was found to be dynamic and at least partially unfolded in our experimental conditions.…”
Section: Discussionsupporting
confidence: 91%
“…A suitable method for the structural characterization of the insoluble ASC aggregates that form at physiological pH conditions is cryo-EM, which recently has provided the first structure of an ASC-PYD filament at nearatomic resolution (16). Filaments of human ASC-PYD feature a helical arrangement along well-defined molecular interfaces, in agreement with other molecular assemblies of death domains (16)(17)(18). An alternative method to determine structures of insoluble protein assemblies at atomic resolution is solid-state NMR spectroscopy under magic-angle-spinning (MAS) conditions (19)(20)(21)(22).…”
Section: Significancementioning
confidence: 89%
“…Previously, it has been suggested that CARD14 mutants associated with psoriasis are less soluble than WT CARD14 (Berki et al, 2015). Additionally, it has been previously described that Bcl10 forms oligomeric structures that can be nucleated by CARD11 (Qiao et al, 2013). It was therefore of interest to determine whether interaction of CARD14 with Bcl10 can induce nucleation and insolubility of the latter.…”
Section: Resultsmentioning
confidence: 99%
“…First, we assessed whether mutation of the CARD14 CARD domain could diminish downstream effects. The CARD14 R38 residue has been previously described to be at the Bcl10-interacting interface, and substitution of arginine R38 with cysteine in the CARD domain was previously reported to lack the ability to activate NF-kB (Jordan, 2012b;Qiao, 2013); therefore, it was anticipated that the R38C mutation would abolish CARD:CARD interactions. Indeed, mutation of the R38 residue in the CARD14 E138A construct completely abrogates the ability of the E138A mutant to interact with Bcl10 (see Figure 1b, Supplementary Figure S1c) and to potently activate NF-kB and AP-1 in HEK293 cells (see Supplementary Figure S1d).…”
Section: Resultsmentioning
confidence: 99%
“…The recruitment domain of MALT1 at its N terminus replaced by the N terminus of API2 is required for this novel interaction. This interaction is specific since no binding was observed between LIMA1a and MALT1 that interacts with its substrates after formation of the CBM signallosome in response to appropriate stimuli 3,7 . We further demonstrated that LIMA1a is proteolytically processed by the paracaspase-mediated activity of API2-MALT1 after binding to the API2 moiety.…”
Section: Discussionmentioning
confidence: 98%