Cited by 287Genetics and Neurodevelopmental DisordersRNA and protein synthesis mechanismsRNA Research and Splicing

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

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Darnell, Jennifer C., Fraser, Claire E., Mostovetsky, Olga, Stefani, Giovanni, Jones, Thomas A., Eddy, Sean R., Darnell, Robert B.·2005·Genes & Development

DOI 10.1101/gad.1276805PMC PMC1080130

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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.

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Authors: Darnell, J. C., Fraser, C. E., Mostovetsky, O., Stefani, G., Jones, T. A., Eddy, S. R., & Darnell, R. B.
Affiliations: Howard Hughes Medical Institute (US)
ORCID: Darnell, Jennifer C.
Stefani, Giovanni
Eddy, Sean R.
Darnell, Robert B.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2005-04-01
Volume: 19
Issue: 8
Pages: 903-918
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.1276805
PMC: PMC1080130
OpenAlex: W2124859239
Cited by: 287
References: 80
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Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed Central (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
Funders: Howard Hughes Medical Institute
Memorial Sloan-Kettering Cancer Center
Weill Cornell Medical College
National Human Genome Research Institute (R01HG001363, R01-HG01363)
National Institute of General Medical Sciences (GM 07739, T32GM007739)
National Institute of Neurological Disorders and Stroke (R01NS040955, R01 NS34389, R01NS034389, NS40955)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD40647, R01HD040647)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords: FMRP, polysomes, RNA-binding proteins, translational regulation, RGG domain, fragile X syndrome, RNA tertiary structure, RNA-protein interactions
MeSH terms: Animals, Base Sequence, Cerebral Cortex, DNA Mutational Analysis, Fragile X Syndrome, Gene Expression Regulation, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Polyribosomes, RNA, Blotting, Western, RNA-Binding Proteins, Sequence Analysis, DNA, Protein Structure, Tertiary, DNA Primers, Base Pairing, Mutation, Missense, Amino Acid Motifs, Electrophoretic Mobility Shift Assay, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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

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