5zi6
The RING domain structure of MEX-3CThe RING domain structure of MEX-3C
Structural highlights
Disease[MEX3C_HUMAN] Genetic variations in MEX3C may be associated with susceptibility to essential hypertension.[1] Function[MEX3C_HUMAN] E3 ubiquitin ligase responsible for the post-transcriptional regulation of common HLA-A allotypes. Binds to the 3' UTR of HLA-A2 mRNA, and regulates its levels by promoting mRNA decay. RNA binding is sufficient to prevent translation, but ubiquitin ligase activity is required for mRNA degradation.[2] [3] Publication Abstract from PubMedMEX-3C, a novel RNA binding E3 ubiquitin ligases, contains two N-terminal heterogeneous nuclear ribonucleoprotein K homology (KH) domains and C-terminal Ring finger domain. Recent evidence has suggested that human MEX-3C has a strong bondage with carcinogenesis and the MEX-3C-mediated ubiquitination of RIG-I is essential for the antiviral innate immune response. Moreover, the Ring finger domain of MEX-3C could regulate the degradation of HLA-A2 (an MHC-I allotype) mRNA with a novel mechanism. However, the structural basis for the ubiquitination catalyzed by hMEX-3C Ring finger domain remains evasive. In this study, we solved the crystal structure of dimeric Ring finger domain of hMEX-3C and compared it with the complex structure of MDM2/MDMX-UbcH5b-Ub. Our ubiquitination assay demonstrated that the Ring finger domain of hMEX-3C acts as a ubiquitin E3 ligase in vitro, cooperating with specific E2 to mediate ubiquitination. Then, we identified several key residues in Ring finger domain of hMEX-3C possibly involved in the interaction with E2-Ub conjugate and analyzed the E3 ligase activities of wild type and mutants at key sites. Additionally, zinc chelation experiments indicated that the intact structural stability is essential for the self-ubiquitination activity of the Ring finger domain of hMEX-3C. Taken together, our studies provided new insight into the mechanism of the Ring finger domain of hMEX-3C that may play an important role in eliciting antiviral immune responses and therapeutic interventions. Structural and functional characterization of hMEX-3C Ring finger domain as an E3 ubiquitin ligase.,Moududee SA, Jiang Y, Gilbert N, Xie G, Xu Z, Wu J, Gong Q, Tang Y, Shi Y Protein Sci. 2018 Sep;27(9):1661-1669. doi: 10.1002/pro.3473. PMID:30095198[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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