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Structure and dynamics of RNA repeat expansions that cause Huntington's Disease and myotonic dystrophy type 1.

08:00 EDT 15th June 2017 | BioPortfolio

Summary of "Structure and dynamics of RNA repeat expansions that cause Huntington's Disease and myotonic dystrophy type 1."

RNA repeat expansions cause a host of incurable, genetically-defined diseases. The most common class of RNA repeats are trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3×CAG)] or r(CUG) [r(3×CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics. The 1 × 1 internal loops of r(3×CAG) are stabilized by one hydrogen bond (cis Watson-Crick/Watson-Crick) AA pairs while those of r(3×CUG) prefer one or two hydrogen bond (cis Watson-Crick/Watson-Crick) UU pairs. Assigned chemical shifts for the residues depended on the identity of neighbors or next nearest neighbors. Additional insights into the dynamics of these RNA constructs were gained by molecular dynamics simulations and a discrete path sampling method. Results indicate that the global structures of the RNA are A-form, and that the loop regions are dynamic. The results will be useful to understand the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics.

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This article was published in the following journal.

Name: Biochemistry
ISSN: 1520-4995
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Membrane glycosylphosphatidylinositol-anchored glycoproteins that may aggregate into rod-like structures. The prion protein (PRNP) gene is characterized by five TANDEM REPEAT SEQUENCES that encode a highly unstable protein region of five octapeptide repeats. Mutations in the repeat region and elsewhere in this gene are associated with CREUTZFELDT-JAKOB DISEASE; FATAL FAMILIAL INSOMNIA; GERSTMANN-STRAUSSLER DISEASE; Huntington disease-like 1, and KURU.

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