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PMID:15805463

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Citation

Darnell, JC, Fraser, CE, Mostovetsky, O, Stefani, G, Jones, TA, Eddy, SR and Darnell, RB (2005) Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes. Genes Dev. 19:903-18

Abstract

Fragile-X mental retardation is caused by loss of function of a single gene encoding the Fragile-X mental retardation protein, FMRP, an RNA-binding protein that harbors two KH-type and one RGG-type RNA-binding domains. Previous studies identified intramolecular G-quartet RNAs as high-affinity targets for the RGG box, but the relationship of RNA binding to FMRP function and mental retardation remains unclear. One severely affected patient harbors a missense mutation (I304N) within the second KH domain (KH2), and some evidence suggests this domain may be involved in the proposed role of FMRP in translational regulation. We now identify the RNA target for the KH2 domain as a sequence-specific element within a complex tertiary structure termed the FMRP kissing complex. We demonstrate that the association of FMRP with brain polyribosomes is abrogated by competition with the FMRP kissing complex RNA, but not by high-affinity G-quartet RNAs. We conclude that mental retardation associated with the I304N mutation, and likely the Fragile-X syndrome more generally, may relate to a crucial role for RNAs harboring the kissing complex motif as targets for FMRP translational regulation.

Links

PubMed PMC1080130 Online version:10.1101/gad.1276805

Keywords

Amino Acid Motifs/genetics; Animals; Base Pairing; Base Sequence; Blotting, Western; Cerebral Cortex/metabolism; DNA Mutational Analysis; DNA Primers; Electrophoretic Mobility Shift Assay; Fragile X Mental Retardation Protein; Fragile X Syndrome/genetics; Gene Expression Regulation; Humans; Mice; Molecular Sequence Data; Mutation, Missense/genetics; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Polyribosomes/metabolism; Protein Structure, Tertiary/physiology; RNA/metabolism; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Sequence Analysis, DNA

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FMR1

enables

GO:0035613: RNA stem-loop binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:0005844: polysome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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