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Crystal structure of the KH1 domain of human RNA-binding E3 ubiquitin-protein ligase MEX-3C complex with RNA

Structural highlights

5www is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.798Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

MEX-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

↑ Guzman B, Cormand B, Ribases M, Gonzalez-Nunez D, Botey A, Poch E. Implication of chromosome 18 in hypertension by sibling pair and association analyses: putative involvement of the RKHD2 gene. Hypertension. 2006 Nov;48(5):883-91. Epub 2006 Oct 2. PMID:17015768 doi:http://dx.doi.org/10.1161/01.HYP.0000244085.52918.a0
↑ Cano F, Bye H, Duncan LM, Buchet-Poyau K, Billaud M, Wills MR, Lehner PJ. The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation. EMBO J. 2012 Aug 29;31(17):3596-606. doi: 10.1038/emboj.2012.218. Epub 2012 Aug, 3. PMID:22863774 doi:http://dx.doi.org/10.1038/emboj.2012.218
↑ Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller MC, Shaikh N, Domingo E, Kanu N, Dewhurst SM, Gronroos E, Chew SK, Rowan AJ, Schenk A, Sheffer M, Howell M, Kschischo M, Behrens A, Helleday T, Bartek J, Tomlinson IP, Swanton C. Replication stress links structural and numerical cancer chromosomal instability. Nature. 2013 Feb 28;494(7438):492-496. doi: 10.1038/nature11935. PMID:23446422 doi:http://dx.doi.org/10.1038/nature11935
↑ Yang L, Wang C, Li F, Zhang J, Nayab A, Wu J, Shi Y, Gong Q. The human RNA-binding protein and E3 ligase MEX-3C binds the MEX-3-recognition element (MRE) motif with high affinity. J Biol Chem. 2017 Aug 14. pii: jbc.M117.797746. doi: 10.1074/jbc.M117.797746. PMID:28808060 doi:http://dx.doi.org/10.1074/jbc.M117.797746

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5www"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the KH1 domain of human RNA-binding E3 ubiquitin-protein ligase MEX-3C complex with RNA==
-<StructureSection load='5www' size='340' side='right' caption='[[5www]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+<StructureSection load='5www' size='340' side='right'caption='[[5www]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5www]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WWW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WWW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5www]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WWW FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5wwx|5wwx]], [[5wwz|5wwz]]</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.798&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5www FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5www OCA], [https://pdbe.org/5www PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5www RCSB], [https://www.ebi.ac.uk/pdbsum/5www PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5www ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5www FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5www OCA], [http://pdbe.org/5www PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5www RCSB], [http://www.ebi.ac.uk/pdbsum/5www PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5www ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/MEX3C_HUMAN MEX3C_HUMAN]] Genetic variations in MEX3C may be associated with susceptibility to essential hypertension.<ref>PMID:17015768</ref>
+[https://www.uniprot.org/uniprot/MEX3C_HUMAN MEX3C_HUMAN] Genetic variations in MEX3C may be associated with susceptibility to essential hypertension.<ref>PMID:17015768</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/MEX3C_HUMAN 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.<ref>PMID:22863774</ref> <ref>PMID:23446422</ref>
+[https://www.uniprot.org/uniprot/MEX3C_HUMAN 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.<ref>PMID:22863774</ref> <ref>PMID:23446422</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: RING-type E3 ubiquitin transferase]]
+[[Category: Homo sapiens]]
-[[Category: Gong, Q]]
+[[Category: Large Structures]]
-[[Category: Li, F]]
+[[Category: Synthetic construct]]
-[[Category: Wang, C]]
+[[Category: Gong Q]]
-[[Category: Yang, L]]
+[[Category: Li F]]
-[[Category: Kh1]]
+[[Category: Wang C]]
-[[Category: Mex-3c]]
+[[Category: Yang L]]
-[[Category: Rna]]
-[[Category: Rna binding protein-rna complex]]

5www

From Proteopedia

Current revision

Crystal structure of the KH1 domain of human RNA-binding E3 ubiquitin-protein ligase MEX-3C complex with RNA

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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