A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P

doi:10.1073/pnas.151231598

A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P

^*Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, B.P. 163, 67404 Illkirch Cedex, Strasbourg, France; ^†Dipartimento di Patologia Umana ed Ereditaria, sez. Biologia Generale e Genetica Medica, Università di Pavia, 27100 Pavia, Italy; and ^‡Dipartimento di Biologia, Università di Roma “Tor Vergata,” 00133 Rome, Italy

Communicated by William T. Greenough, University of Illinois at Urbana–Champaign, Urbana, IL (received for review January 22, 2001)

Abstract

The absence of the fragile X mental retardation protein (FMRP), encoded by the FMR1 gene, is responsible for pathologic manifestations in the Fragile X Syndrome, the most frequent cause of inherited mental retardation. FMRP is an RNA-binding protein associated with polysomes as part of a messenger ribonucleoprotein (mRNP) complex. Although its function is poorly understood, various observations suggest a role in local protein translation at neuronal dendrites and in dendritic spine maturation. We present here the identification of CYFIP1/2 (Cytoplasmic FMRP Interacting Proteins) as FMRP interactors. CYFIP1/2 share 88% amino acid sequence identity and represent the two members in humans of a highly conserved protein family. Remarkably, whereas CYFIP2 also interacts with the FMRP-related proteins FXR1P/2P, CYFIP1 interacts exclusively with FMRP. FMRP–CYFIP interaction involves the domain of FMRP also mediating homo- and heteromerization, thus suggesting a competition between interaction among the FXR proteins and interaction with CYFIP. CYFIP1/2 are proteins of unknown function, but CYFIP1 has recently been shown to interact with the small GTPase Rac1, which is implicated in development and maintenance of neuronal structures. Consistent with FMRP and Rac1 localization in dendritic fine structures, CYFIP1/2 are present in synaptosomal extracts.

Footnotes

↵ § To whom reprint requests should be addressed. E-mail: mandeljl{at}igbmc.u-strasbg.fr.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. D38549 (KIAA0068/human CYFIP1), AF160973 (PIR121/human CYFIP2), AF072697 (shyc/mouse CYFIP1), AF334144 (mouse CYFIP2), AY017342 (zebrafish CYFIP), AY017343 (fly CYFIP), and AF038619 (worm CYFIP)].
Abbreviations:

mRNP,

messenger ribonucleoprotein;

FMR1,

fragile X mental retardation gene;

FMRP,

fragile X mental retardation protein;

FXR1 and -2,

FMR1-related genes 1 and 2;

FXR1P/2P,

FXR1 and -2 proteins;

β-gal,

β-galactosidase;

GST-pd,

glutathione S-transferase pull-down;

GFP,

green fluorescent protein;

X-gal,

5-bromo-4-chloro-3-indolyl β-d-galactoside;

pAb,

polyclonal antibodies