5gpp
From Proteopedia
Crystal structure of zebrafish ASC PYD domain
Structural highlights
FunctionMALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.ASC_DANRE Functions as key mediator in apoptosis and inflammation (PubMed:12464617, PubMed:30150286). Promotes caspase-mediated apoptosis (PubMed:12464617). Induces proteolytic processing of caspa and caspa-dependent apoptosis (PubMed:12464617). Involved in innate immune response by acting as an integral adapter in the assembly of various inflammasomes which recruit and activate caspase-1 leading to processing and secretion of pro-inflammatory cytokines (PubMed:30150286). Caspase-1-dependent inflammation leads to macrophage pyroptosis, a form of cell death (By similarity). The function as activating adapter in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions (PubMed:30150286). Clustered PYCARD nucleates the formation of caspase-1 filaments through the interaction of their respective CARD domains, acting as a platform for of caspase-1 polymerization (By similarity). Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome (By similarity).[UniProtKB:Q9ULZ3][1] [2] Publication Abstract from PubMedThe zebrafish genome encodes homologs for most of the proteins involved in inflammatory pathways; however, the molecular components and activation mechanisms of fish inflammasomes are largely unknown. ASC [apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD)] is the only adaptor involved in the formation of multiple types of inflammasomes. Here, we demonstrate that zASC is also involved in inflammasome activation in zebrafish. When overexpressed in vitro and in vivo in zebrafish, both the zASC and zASC pyrin domain (PYD) proteins form speck and filament structures. Importantly, the crystal structures of the N-terminal PYD and C-terminal CARD of zebrafish ASC were determined independently as two separate entities fused to maltose-binding protein. Structure-guided mutagenesis revealed the functional relevance of the PYD hydrophilic surface found in the crystal lattice. Finally, the fish caspase-1 homolog Caspy, but not the caspase-4/11 homolog Caspy2, interacts with zASC through homotypic PYD-PYD interactions, which differ from those in mammals. These observations establish the conserved and unique structural/functional features of the zASC-dependent inflammasome pathway. DATABASE: Structural data are available in the PDB under accession numbers 5GPP and 5GPQ. Functional and structural characterization of zebrafish ASC.,Li Y, Huang Y, Cao X, Yin X, Jin X, Liu S, Jiang J, Jiang W, Xiao TS, Zhou R, Cai G, Hu B, Jin T FEBS J. 2018 Jul;285(14):2691-2707. doi: 10.1111/febs.14514. Epub 2018 Jun 14. PMID:29791979[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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