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Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1

2008; Nature Portfolio; Volume: 15; Issue: 12 Linguagem: Inglês

10.1038/nsmb.1519

1545-9993

Marianna Teplova, Dinshaw J. Patel,

RNA and protein synthesis mechanisms

Muscleblind-like (MBNL) proteins have been implicated in alternative-splicing regulation during development, and altered levels of these proteins have been implicated in myotonic dystrophy. The structure of the MBNL1 zinc finger domains in complex with RNA indicates how the target sequence is recognized and suggests that an antiparallel arrangement of the zinc fingers causes a trajectory reversal in the pre-mRNA target. The potential role of such generated looped segments in alternative splicing is discussed. 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.