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PMID: 15805463 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Genes & development ·Vol. 19 ·No. 8 ·2005-04-15 ·Pages 903-18

Darnell JC, Fraser CE, Mostovetsky O, Stefani G, Jones TA, Eddy SR, Darnell RB

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.

MeSH Terms
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,metabolism Polyribosomes/metabolism Protein Structure, Tertiary/physiology RNA/metabolism RNA-Binding Proteins/genetics,metabolism Sequence Analysis, DNA
Chemicals
DNA Primers FMR1 protein, human Fmr1 protein, mouse Nerve Tissue Proteins RNA-Binding Proteins Fragile X Mental Retardation Protein RNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Darnell Jennifer C
Howard Hughes Medical Institute and Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. darneje@rockefeller.edu
Fraser Claire E
Mostovetsky Olga
Stefani Giovanni
Jones Thomas A
Eddy Sean R
Darnell Robert B
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1276805
Email
darneje@rockefeller.edu
Published
2005-04-15
Epub
2005-00-01
Pages
903-18
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC1080130
Subset
IM
Grants
NINDS NIH HHS · NS40955 · United States
NIGMS NIH HHS · GM07739 · United States
NINDS NIH HHS · R01 NS34389 · United States
NINDS NIH HHS · R01 NS040955 · United States
NICHD NIH HHS · R01 HD040647 · United States
NINDS NIH HHS · R01 NS034389 · United States
NICHD NIH HHS · R01 HD40647 · United States
NHGRI NIH HHS · R01 HG001363 · United States
NIGMS NIH HHS · T32 GM007739 · United States
NHGRI NIH HHS · R01 HG01363 · United States
External Links
PubMed source DOI: 10.1101/gad.1276805 PMC Full Text View journal details
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