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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
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[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
- ↑ Teplova M, Patel DJ. Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1. Nat Struct Mol Biol. 2008 Dec;15(12):1343-51. Epub 2008 Nov 30. PMID:19043415 doi:10.1038/nsmb.1519
