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Crystal structure of the KH2 domain of human RNA-binding E3 ubiquitin-protein ligase MEX-3CCrystal structure of the KH2 domain of human RNA-binding E3 ubiquitin-protein ligase MEX-3C
Structural highlights
DiseaseMEX3C_HUMAN Genetic variations in MEX3C may be associated with susceptibility to essential hypertension.[1] FunctionMEX3C_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-3 is a KH domain-containing RNA-binding protein, first identified as a translational repressor in Caenorhabditis elegans, while its four orthologs (MEX-3A-D) in human and mouse were subsequently found to have E3 ubiquitin ligase activity mediated by a RING domain and critical for RNA degradation. Current evidence implicates human MEX-3C in many essential biological processes and suggests a strong connection with immune diseases and carcinogenesis. The highly conserved dual KH domains in MEX-3 proteins enable RNA binding and are essential for the recognition of the 3' UTR and posttranscriptional regulation of MEX-3 target transcripts. However, the molecular mechanisms of translational repression and the consensus RNA sequence recognized by the MEX-3C KH domain are unknown. Here, using X-ray crystallography and isothermal titration calorimetry, we investigated the RNA-binding activity and selectivity of human MEX-3C dual KH domains. Our high-resolution crystal structures of individual KH domains complexed with a noncanonical U-rich and a GA-rich RNA sequences revealed that the KH1/2 domains of hMEX-3C bound MRE10, a 10-mer RNA (5'-CAGAGUUUAG-3') consisting of an eight-nucleotide MEX-3-recognition element (MRE) motif, with high affinity. Of note, we also identified a consensus RNA motif recognized by human MEX-3C. The potential RNA-binding sites in the 3' UTR of the human leukocyte antigen serotype (HLA-A2) mRNA were mapped with this RNA-binding motif and were further confirmed by fluorescence polarization. The binding motif identified here will provide valuable information for future investigations of the functional pathways controlled by human MEX-3C and for predicting potential mRNAs regulated by this enzyme. The human RNA-binding protein and E3 ligase MEX-3C binds the MEX-3-recognition element (MRE) motif with high affinity.,Yang L, Wang C, Li F, Zhang J, Nayab A, Wu J, Shi Y, Gong Q J Biol Chem. 2017 Aug 14. pii: jbc.M117.797746. doi: 10.1074/jbc.M117.797746. PMID:28808060[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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