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| | ==Solution structure of the zinc fingers 1 and 2 of MBNL1 in complex with human cardiac troponin T pre-mRNA== | | ==Solution structure of the zinc fingers 1 and 2 of MBNL1 in complex with human cardiac troponin T pre-mRNA== |
| - | <StructureSection load='5u9b' size='340' side='right'caption='[[5u9b]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='5u9b' size='340' side='right'caption='[[5u9b]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5u9b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U9B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U9B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5u9b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U9B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U9B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u6h|5u6h]], [[5u6l|5u6l]]</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=5u9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u9b OCA], [https://pdbe.org/5u9b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u9b RCSB], [https://www.ebi.ac.uk/pdbsum/5u9b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u9b ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MBNL1, EXP, KIAA0428, MBNL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5u9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u9b OCA], [http://pdbe.org/5u9b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u9b RCSB], [http://www.ebi.ac.uk/pdbsum/5u9b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u9b ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/MBNL1_HUMAN MBNL1_HUMAN]] Plays a role in the pathogenesis of dystrophia myotonica type 1 (DM1) [MIM:[http://omim.org/entry/160900 160900]]. A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. Note=In muscle cells from DM1 patients, MBNL1 is sequestered by DMPK RNAs containing CUG triplet repeat expansions. MBNL1 binding is proportional to repeat length consistent with the direct correlation between the length of repeat expansion and disease severity. | + | [https://www.uniprot.org/uniprot/MBNL1_HUMAN MBNL1_HUMAN] Plays a role in the pathogenesis of dystrophia myotonica type 1 (DM1) [MIM:[https://omim.org/entry/160900 160900]. A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. Note=In muscle cells from DM1 patients, MBNL1 is sequestered by DMPK RNAs containing CUG triplet repeat expansions. MBNL1 binding is proportional to repeat length consistent with the direct correlation between the length of repeat expansion and disease severity. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MBNL1_HUMAN MBNL1_HUMAN]] Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. Regulates the TNNT2 exon 5 skipping through competition with U2AF2. Inhibits the formation of the spliceosome A complex on intron 4 of TNNT2 pre-mRNA. Binds to the stem-loop structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Binds to the 5'-YGCU(U/G)Y-3'consensus sequence. Binds to the IR RNA. Binds to expanded CUG repeat RNA, which folds into a hairpin structure containing GC base pairs and bulged, unpaired U residues.<ref>PMID:10970838</ref> <ref>PMID:15257297</ref> <ref>PMID:16946708</ref> <ref>PMID:18335541</ref> <ref>PMID:19470458</ref> | + | [https://www.uniprot.org/uniprot/MBNL1_HUMAN MBNL1_HUMAN] Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. Regulates the TNNT2 exon 5 skipping through competition with U2AF2. Inhibits the formation of the spliceosome A complex on intron 4 of TNNT2 pre-mRNA. Binds to the stem-loop structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Binds to the 5'-YGCU(U/G)Y-3'consensus sequence. Binds to the IR RNA. Binds to expanded CUG repeat RNA, which folds into a hairpin structure containing GC base pairs and bulged, unpaired U residues.<ref>PMID:10970838</ref> <ref>PMID:15257297</ref> <ref>PMID:16946708</ref> <ref>PMID:18335541</ref> <ref>PMID:19470458</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dyson, H J]] | + | [[Category: Dyson HJ]] |
| - | [[Category: Martinez-Yamout, M M]] | + | [[Category: Martinez-Yamout MM]] |
| - | [[Category: Park, S]] | + | [[Category: Park S]] |
| - | [[Category: Phukan, P D]] | + | [[Category: Phukan PD]] |
| - | [[Category: Wright, P E]] | + | [[Category: Wright PE]] |
| - | [[Category: Zeeb, M]] | + | [[Category: Zeeb M]] |
| - | [[Category: Rna binding protein-rna complex]]
| + | |
| - | [[Category: Structure from molmol]]
| + | |
| - | [[Category: Zinc fingers rna-binding]]
| + | |
| Structural highlights
Disease
MBNL1_HUMAN Plays a role in the pathogenesis of dystrophia myotonica type 1 (DM1) [MIM:160900. A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. Note=In muscle cells from DM1 patients, MBNL1 is sequestered by DMPK RNAs containing CUG triplet repeat expansions. MBNL1 binding is proportional to repeat length consistent with the direct correlation between the length of repeat expansion and disease severity.
Function
MBNL1_HUMAN Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. Regulates the TNNT2 exon 5 skipping through competition with U2AF2. Inhibits the formation of the spliceosome A complex on intron 4 of TNNT2 pre-mRNA. Binds to the stem-loop structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Binds to the 5'-YGCU(U/G)Y-3'consensus sequence. Binds to the IR RNA. Binds to expanded CUG repeat RNA, which folds into a hairpin structure containing GC base pairs and bulged, unpaired U residues.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The human muscleblind-like proteins (MBNL) regulate tissue-specific splicing by targeting cardiac troponin T and other pre-mRNAs; aberrant targeting of CUG and CCUG repeat expansions frequently accompanies the neuromuscular disease myotonic dystrophy. We show, using biolayer interferometry (Octet), and NMR spectroscopy, that the zinc finger domains of MBNL isoform 1 (MBNL1) are necessary and sufficient for binding CGCU sequences within the pre-mRNA of human cardiac troponin T (hcTnT). Protein constructs containing zinc fingers 1 and 2 (zf12) and zinc fingers 3 and 4 (zf34) of MBNL1 each fold into a compact globular tandem zinc finger structure that participates in RNA binding. NMR spectra show that the stoichiometry of the interaction between zf12 or zf34 and the CGCU sequence is 1:1, and that the RNA is single-stranded in the complex. The individual zinc fingers within zf12 or zf34 are non-equivalent: the primary RNA binding surface is formed in each pair by the second zinc finger (zf2 or zf4), which interacts with the CGCU RNA sequence. The NMR structure of the complex between zf12 and a 15-base RNA of sequence 95GUCUCGCUUUUCCCC109, containing a single CGCU element shows the single-stranded RNA wrapped around zf2 and extending to bind to the C-terminal helix. Bases C101, U102 and U103 make well defined and highly ordered contacts with the protein while neighboring bases are less well-ordered in the complex. Binding of the MBNL zinc fingers to cardiac troponin T pre-mRNA is specific and relatively simple, unlike the complex multiple dimer-trimer stoichiometries postulated in some previous studies.
Structural basis for interaction of the tandem zinc finger domains of human muscleblind with cognate RNA from human cardiac troponin T.,Park S, Phukan PD, Zeeb M, Martinez-Yamout MA, Dyson HJ, Wright PE Biochemistry. 2017 Jul 18. doi: 10.1021/acs.biochem.7b00484. PMID:28718627[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 2000 Sep 1;19(17):4439-48. PMID:10970838 doi:10.1093/emboj/19.17.4439
- ↑ Ho TH, Charlet-B N, Poulos MG, Singh G, Swanson MS, Cooper TA. Muscleblind proteins regulate alternative splicing. EMBO J. 2004 Aug 4;23(15):3103-12. Epub 2004 Jul 15. PMID:15257297 doi:10.1038/sj.emboj.7600300
- ↑ Paul S, Dansithong W, Kim D, Rossi J, Webster NJ, Comai L, Reddy S. Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing. EMBO J. 2006 Sep 20;25(18):4271-83. Epub 2006 Aug 31. PMID:16946708 doi:10.1038/sj.emboj.7601296
- ↑ Onishi H, Kino Y, Morita T, Futai E, Sasagawa N, Ishiura S. MBNL1 associates with YB-1 in cytoplasmic stress granules. J Neurosci Res. 2008 Jul;86(9):1994-2002. doi: 10.1002/jnr.21655. PMID:18335541 doi:10.1002/jnr.21655
- ↑ Warf MB, Diegel JV, von Hippel PH, Berglund JA. The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9203-8. doi:, 10.1073/pnas.0900342106. Epub 2009 May 26. PMID:19470458 doi:10.1073/pnas.0900342106
- ↑ Park S, Phukan PD, Zeeb M, Martinez-Yamout MA, Dyson HJ, Wright PE. Structural basis for interaction of the tandem zinc finger domains of human muscleblind with cognate RNA from human cardiac troponin T. Biochemistry. 2017 Jul 18. doi: 10.1021/acs.biochem.7b00484. PMID:28718627 doi:http://dx.doi.org/10.1021/acs.biochem.7b00484
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