Analysis of domains affecting intracellular localization of the FMRP protein

Neurobiology of Disease
B BardoniJ L Mandel

Abstract

Fragile X syndrome is the most frequent form of inherited mental retardation and it is caused by deficiency of FMRP, the protein encoded by the FMR1 gene. FMRP is a RNA binding protein of unknown function which is associated with ribosomes. FMRP is found in the cytoplasm, but it is endowed with a nuclear export signal (NES), encoded by exon 14, and a nuclear localization signal (NLS). Characterization of the FMRP NES and NLS domains is presented here. We show by site-directed mutagenesis that three leucine residues in exon 14 are functionally important for the cytoplasmic localization of FMRP. Changing these leucines to serine resulted in a nuclear localization, while another nonconservative change (leucine to tyrosine) did not show such an effect. We also show that the NLS activity is localized between residues 115 and 150, a region that lacks stretches of basic residues. Such stretches are typical of nuclear localization signals that act through the important alpha pathway. The region between residues 151 and 196 can reinforce the NLS activity. A truncated construct containing the N-terminal region of FMRP (residues 1-114) is strikingly concentrated in the nucleus. This suggests that it may contain a domain of strong affinity...Continue Reading

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Citations

Jul 26, 2008·Nucleic Acids Research·Marie-Cécile DidiotHervé Moine
Oct 22, 2008·Molecular and Cellular Biology·Miri KimStephanie Ceman
Jul 23, 2008·Molecular Reproduction and Development·Namdori R MtangoKeith E Latham
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Jul 24, 2012·Journal of Neurochemistry·Se Jin JeonChan Young Shin
Dec 14, 2004·Gene·Jasenka Guduric-FuchsUri Frank
Jan 28, 2014·Neuroscience and Biobehavioral Reviews·Thomas MaurinBarbara Bardoni
Oct 1, 2011·Biomolecular Concepts·Claudia Winograd, Stephanie Ceman
Mar 12, 2013·Neuron·David L NelsonStephen T Warren
Nov 24, 2001·Brain Research Bulletin·B BardoniJ L Mandel
Feb 17, 2001·American Journal of Medical Genetics·B BardoniG S Fisch
Nov 13, 2004·Neuroreport·Massimiliano VeneriClaudia Bagni
Nov 5, 1999·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·E W Khandjian
Jun 12, 2020·The FEBS Journal·Mohamed S TahaMohammad R Ahmadian
Sep 4, 2020·Critical Reviews in Biochemistry and Molecular Biology·Mrinmoyee MajumderViswanathan Palanisamy
May 17, 2017·International Journal of Molecular Sciences·Valeria SpecchiaMaria Pia Bozzetti
Sep 19, 2018·Molecular Neurobiology·Cara J Westmark
Jan 9, 2019·Frontiers in Molecular Biosciences·Thomas Maurin, Barbara Bardoni
May 2, 2018·Frontiers in Molecular Neuroscience·Małgorzata DrozdMaria Capovilla

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