Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes

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 target...

Full description

Saved in:
Bibliographic Details
Published in:Genes & development 2005-04, Vol.19 (8), p.903-918
Main Authors: Darnell, Jennifer C, Fraser, Claire E, Mostovetsky, Olga, Stefani, Giovanni, Jones, Thomas A, Eddy, Sean R, Darnell, Robert B
Format: Article
Language:English
Subjects:
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
Research Papers
RNA - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Sequence Analysis, DNA
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1276805