6jx6
From Proteopedia
Tetrameric form of Smac
Structural highlights
DiseaseDBLOH_HUMAN Defects in DIABLO are the cause of deafness autosomal dominant type 64 (DFNA64) [MIM:614152. DFNA64 is a form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.[1] FunctionDBLOH_HUMAN Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). Inhibits the activity of BIRC6/bruce by inhibiting its binding to caspases. Isoform 3 attenuates the stability and apoptosis-inhibiting activity of XIAP/BIRC4 by promoting XIAP/BIRC4 ubiquitination and degradation through the ubiquitin-proteasome pathway. Isoform 3 also disrupts XIAP/BIRC4 interacting with processed caspase-9 and promotes caspase-3 activation. Isoform 1 is defective in the capacity to down-regulate the XIAP/BIRC4 abundance.[2] [3] [4] Publication Abstract from PubMedThe HECT E3 ligase family comprises three subfamilies: NEDD4 E3 ubiquitin protein ligase (NEDD4), HECT and RLD domain-containing E3 ubiquitin protein ligase (HERC), and "other." Most previous studies have focused on the NEDD4 subfamily. Apoptosis-resistant E3 ligase 1 (AREL1) belongs to "other" subfamily HECT that inhibits apoptosis by ubiquitinating and degrading proapoptotic proteins. Here, we report the crystal structure of the extended HECT domain of AREL1 (436-823 aa) at 2.4 A resolution and its ubiquitination of the proapoptotic protein second mitochondria-derived activator of caspase (SMAC). We found that the extended HECT domain adopts an inverted, T-shaped, bilobed conformation and harbors an additional loop (567-573 aa) absent in all other HECT members. We also show that the N-terminal extended region (436-482 aa) preceding the HECT domain is indispensable for its stability and activity and that without this region, the HECT domain becomes inactive. AREL1 ubiquitinated SMAC, primarily on Lys-62 and Lys-191. We solved the crystal structure of tetrameric form of SMAC to 2.8 A resolution, revealing the Lys-62 and Lys-191 locations. The AREL1 HECT domain assembled Lys-33-, Lys-48- and Lys-63-linked polyubiquitin chains. Moreover, E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. Finally, an AREL1-specific ubiquitin variant inhibited SMAC ubiquitination in vitro. Our findings may assist in the development of AREL1 inhibitors that block its anti-apoptotic activity in cancer. Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro.,Singh S, Ng J, Nayak D, Sivaraman J J Biol Chem. 2019 Nov 15. pii: RA119.010327. doi: 10.1074/jbc.RA119.010327. PMID:31732561[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Nayak D | Ng J | Singh S | Sivaraman J
