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<StructureSection load='3d2n' size='340' side='right'caption='[[3d2n]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='3d2n' size='340' side='right'caption='[[3d2n]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3d2n]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D2N FirstGlance]. <br>
<table><tr><td colspan='2'>[[3d2n]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D2N FirstGlance]. <br>
</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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3d2q|3d2q]], [[3d2s|3d2s]]</div></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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MBNL1, EXP, KIAA0428, MBNL ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3d2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d2n OCA], [https://pdbe.org/3d2n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d2n RCSB], [https://www.ebi.ac.uk/pdbsum/3d2n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d2n ProSAT]</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=3d2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d2n OCA], [https://pdbe.org/3d2n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d2n RCSB], [https://www.ebi.ac.uk/pdbsum/3d2n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d2n ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[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.  
[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 ==
[[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>
[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>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3d2n ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3d2n ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Muscleblind-like (MBNL) proteins, regulators of developmentally programmed alternative splicing, harbor tandem CCCH zinc-finger (ZnF) domains that target pre-mRNAs containing YGCU(U/G)Y sequence elements (where Y is a pyrimidine). In myotonic dystrophy, reduced levels of MBNL proteins lead to aberrant alternative splicing of a subset of pre-mRNAs. The crystal structure of MBNL1 ZnF3/4 bound to r(CGCUGU) establishes that both ZnF3 and ZnF4 target GC steps, with site-specific recognition mediated by a network of hydrogen bonds formed primarily with main chain groups of the protein. The relative alignment of ZnF3 and ZnF4 domains is dictated by the topology of the interdomain linker, with a resulting antiparallel orientation of bound GC elements, supportive of a chain-reversal loop trajectory for MBNL1-bound pre-mRNA targets. We anticipate that MBNL1-mediated targeting of looped RNA segments proximal to splice-site junctions could contribute to pre-mRNA alternative-splicing regulation.
Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1.,Teplova M, Patel DJ Nat Struct Mol Biol. 2008 Dec;15(12):1343-51. Epub 2008 Nov 30. PMID:19043415<ref>PMID:19043415</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3d2n" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Patel, D J]]
[[Category: Patel DJ]]
[[Category: Teplova, M]]
[[Category: Teplova M]]
[[Category: Alternative splicing]]
[[Category: Metal binding]]
[[Category: Metal-binding]]
[[Category: Nucleus]]
[[Category: Rna binding protein]]
[[Category: Rna-binding]]
[[Category: Tandem zinc finger domain]]
[[Category: Zinc]]
[[Category: Zinc-finger]]

Latest revision as of 09:39, 21 February 2024

Crystal structure of MBNL1 tandem zinc finger 1 and 2 domain

3d2n, resolution 2.70Å

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