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Synaptic functional regulator FMR1



Rattus norvegicus (Rat)
Reviewed-Annotation score: -Experimental evidence at protein leveli


Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs (PubMed:9144248). Plays a role in the alternative splicing of its own mRNA (By similarity). Plays a role in mRNA nuclear export (By similarity). Together with export factor NXF2, is involved in the regulation of the NXF1 mRNA stability in neurons (By similarity). Stabilizes the scaffolding postsynaptic density protein DLG4/PSD-95 and the myelin basic protein MBP mRNAs in hippocampal neurons and glial cells, respectively; this stabilization is further increased in response to metabotropic glutamate receptor (mGluR) stimulation (By similarity). Plays a role in selective delivery of a subset of dendritic mRNAs to synaptic sites in response to mGluR activation in a kinesin-dependent manner (By similarity). Plays a role as a repressor of mRNA translation during the transport of dendritic mRNAs to postnyaptic dendritic spines (PubMed:9144248). Component of the CYFIP1-EIF4E-FMR1 complex which blocks cap-dependent mRNA translation initiation (By similarity). Represses mRNA translation by stalling ribosomal translocation during elongation (By similarity). Reports are contradictory with regards to its ability to mediate translation inhibition of (MBP) mRNA in oligodendrocytes (By similarity). Also involved in the recruitment of the RNA helicase MOV10 to a subset of mRNAs and hence regulates microRNA (miRNA)-mediated translational repression by AGO2 (By similarity). Facilitates the assembly of miRNAs on specific target mRNAs (By similarity). Plays also a role as an activator of mRNA translation of a subset of dendritic mRNAs at synapses (By similarity). In response to mGluR stimulation, FMR1-target mRNAs are rapidly derepressed, allowing for local translation at synapses (By similarity). Binds to a large subset of dendritic mRNAs that encode a myriad of proteins involved in pre- and postsynaptic functions (By similarity). Binds to 5'-ACU[GU]-3' and/or 5'-[AU]GGA-3' RNA consensus sequences within mRNA targets, mainly at coding sequence (CDS) and 3'-untranslated region (UTR) and less frequently at 5'-UTR (By similarity). Binds to intramolecular G-quadruplex structures in the 5'- or 3'-UTRs of mRNA targets (By similarity). Binds to G-quadruplex structures in the 3'-UTR of its own mRNA (By similarity). Binds also to RNA ligands harboring a kissing complex (kc) structure; this binding may mediate the association of FMR1 with polyribosomes (By similarity). Binds mRNAs containing U-rich target sequences (By similarity). Binds to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the 5'-UTR region of superoxide dismutase SOD1 mRNA (By similarity). Binds to the dendritic, small non-coding brain cytoplasmic RNA 1 (BC1); which may increase the association of the CYFIP1-EIF4E-FMR1 complex to FMR1 target mRNAs at synapses (By similarity). Associates with export factor NXF1 mRNA-containing ribonucleoprotein particles (mRNPs) in a NXF2-dependent manner (By similarity). Binds to a subset of miRNAs in the brain (By similarity). May associate with nascent transcripts in a nuclear protein NXF1-dependent manner (By similarity). In vitro, binds to RNA homopolymer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (By similarity). Moreover, plays a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity (By similarity). Negatively regulates the voltage-dependent calcium channel current density in soma and presynaptic terminals of dorsal root ganglion (DRG) neurons, and hence regulates synaptic vesicle exocytosis (PubMed:24709664). Modulates the voltage-dependent calcium channel CACNA1B expression at the plasma membrane by targeting the channels for proteosomal degradation (By similarity). Plays a role in regulation of MAP1B-dependent microtubule dynamics during neuronal development (By similarity). Recently, has been shown to play a translation-independent role in the modulation of presynaptic action potential (AP) duration and neurotransmitter release via large-conductance calcium-activated potassium (BK) channels in hippocampal and cortical excitatory neurons (By similarity). Finally, FMR1 may be involved in the control of DNA damage response (DDR) mechanisms through the regulation of ATR-dependent signaling pathways such as histone H2AFX/H2A.x and BRCA1 phosphorylations (By similarity).By similarity2 Publications

GO - Molecular functioni

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • cellular response to hydroxyurea Source: UniProtKB
  • cellular response to monosodium glutamate Source: RGD
  • cellular response to potassium ion Source: RGD
  • cellular response to UV Source: UniProtKB
  • detection of mechanical stimulus involved in sensory perception Source: RGD
  • gene silencing by RNA Source: UniProtKB-KW
  • glutamate receptor signaling pathway Source: UniProtKB
  • mRNA processing Source: UniProtKB-KW
  • mRNA transport Source: UniProtKB
  • negative regulation of cytoplasmic translation Source: UniProtKB
  • negative regulation of gene expression Source: RGD
  • negative regulation of long term synaptic depression Source: UniProtKB
  • negative regulation of neuron apoptotic process Source: RGD
  • negative regulation of neuron differentiation Source: RGD
  • negative regulation of protein processing Source: RGD
  • negative regulation of receptor internalization Source: RGD
  • negative regulation of synaptic vesicle exocytosis Source: UniProtKB
  • negative regulation of translation Source: UniProtKB
  • negative regulation of translational initiation Source: UniProtKB
  • negative regulation of voltage-gated calcium channel activity Source: UniProtKB
  • neuron development Source: RGD
  • ovarian follicle development Source: RGD
  • positive regulation of dendritic spine development Source: UniProtKB
  • positive regulation of filopodium assembly Source: UniProtKB
  • positive regulation of gene expression Source: RGD
  • positive regulation of gene silencing by miRNA Source: UniProtKB
  • positive regulation of histone phosphorylation Source: UniProtKB
  • positive regulation of mRNA binding Source: UniProtKB
  • positive regulation of proteasomal protein catabolic process Source: UniProtKB
  • positive regulation of protein phosphorylation Source: RGD
  • positive regulation of receptor internalization Source: UniProtKB
  • positive regulation of response to DNA damage stimulus Source: UniProtKB
  • positive regulation of translation Source: UniProtKB
  • regulation of alternative mRNA splicing, via spliceosome Source: UniProtKB
  • regulation of dendritic spine development Source: UniProtKB
  • regulation of filopodium assembly Source: UniProtKB
  • regulation of gene silencing by miRNA Source: UniProtKB
  • regulation of mRNA stability Source: UniProtKB
  • regulation of neuronal action potential Source: UniProtKB
  • regulation of neurotransmitter secretion Source: UniProtKB
  • regulation of translation Source: RGD
  • response to activity Source: RGD
  • response to cocaine Source: RGD
  • response to electrical stimulus Source: RGD
  • response to gonadotropin Source: RGD
  • response to interleukin-1 Source: RGD
  • response to light stimulus Source: RGD
  • RNA splicing Source: UniProtKB-KW


Molecular functionActivator, Repressor, Ribonucleoprotein, RNA-binding
Biological processDNA damage, mRNA processing, mRNA splicing, mRNA transport, Neurogenesis, RNA-mediated gene silencing, Translation regulation, Transport

Names & Taxonomyi

Protein namesi
Recommended name:
Synaptic functional regulator FMR1Curated
Alternative name(s):
Fragile X mental retardation protein 1 homologImported
Short name:
FMRP1 Publication
Short name:
Protein FMR-1By similarity
Gene namesi
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
  • UP000002494 Componenti: Chromosome X

Organism-specific databases

RGDi2623 Fmr1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Centromere, Chromosome, Cytoplasm, Membrane, Nucleus, Postsynaptic cell membrane, Synapse, Synaptosome

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003421851 – 593Synaptic functional regulator FMR1Add BLAST593

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineBy similarity1
Modified residuei336PhosphoserineCombined sources1
Modified residuei337PhosphoserineCombined sources1
Modified residuei347PhosphoserineCombined sources1
Modified residuei349PhosphoserineCombined sources1
Modified residuei350PhosphoserineCombined sources1
Modified residuei369PhosphoserineBy similarity1
Modified residuei441PhosphothreonineBy similarity1
Modified residuei449Omega-N-methylarginineBy similarity1
Modified residuei478PhosphoserineBy similarity1
Modified residuei522Omega-N-methylarginine; alternateBy similarity1
Modified residuei522Omega-N-methylated arginine; alternateBy similarity1
Modified residuei581PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated on several serine residues. Phosphorylation at Ser-478 is required for phosphorylation of other nearby serine residues. Phosphorylation has no effect on the binding of individual mRNA species, but may affect the association with polyribosome. Unphosphorylated FMR1 is associated with actively translating polyribosome, whereas a fraction of phosphorylated FMR1 is associated with apparently stalled polyribosome. Dephosphorylation by an activated phosphatase may release the FMR1-mediated translational repression and allow synthesis of a locally required protein at snypases.By similarity
Monoubiquitinated. Polyubiquitinated. Ubiquitinated and targeted for proteasomal degradation after activation of metabotropic glutamate receptor (mGluR).By similarity
Methylated; methylation is necessary for heterodimerization with FXR1, association with polyribosomes, recruitment into stress granules and translation of FMR1 target mRNAs. Methylated by PRMT1, PRMT3 and PRMT4, in vitro.By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases


PTM databases



Tissue specificityi

Expressed in brain (PubMed:9030614). Expressed in neurons (PubMed:9030614). Expressed in mature oligodendrocytes (OLGs) (PubMed:23891804). Expressed in oligodendroglia progenitor cells (OPCs) and immature oligodendrocytes (OLGs) in the neonatal brain (at protein level) (PubMed:14613971).3 Publications


Up-regulated in response to the activation of group I metabotropic glutamate receptors at synapses (PubMed:9144248). Rapidly and transiently up-regulated in response to light exposure in the cell bodies and dendrites of visual cortical neurons (at protein level) (PubMed:15564573).2 Publications

Gene expression databases

ExpressionAtlasiQ80WE1 baseline and differential


Subunit structurei

Homodimer (By similarity). Forms heterodimer with FXR1; heterodimerization occurs in a methylation-dependent manner (By similarity). Forms heterodimer with FXR2 (By similarity). Homooligomer (By similarity). Component of the CYFIP1-EIF4E-FMR1 complex at least composed of CYFIP, EIF4E and FMR1; this mRNA cap binding complex formation increases in presence of the brain cytoplasmic RNA BC1 and is dynamically regulated in an activity-dependent manner to repress and then possibly release dendritic mRNAs for translation in response to mGluR stimulation (By similarity). Associates with the SMN core complex that contains SMN, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP (By similarity). Part of a ribonucleoprotein complex with AGO2/EIF2C2 and miRNAs (By similarity). Interacts with AGO2/EIF2C2 (By similarity). Interacts (via C-terminus) with CACNA1B; this interaction induces a deacrease in the number of presynaptic functional CACNA1B channels at the cell surface (PubMed:24709664). Interacts with CYFIP1; this interaction recruits CYFIP1 to capped mRNA. Interacts with CYFIP2 (By similarity). Interacts with EIF5; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with dynein (By similarity). Interacts with FXR1 and FXR2 (By similarity). Interacts with methylated histone H3 (By similarity). Interacts with IGF2BP1; this interaction allows to recruit IGF2BP1 to mRNA in a FMR1-dependent manner (By similarity). Interacts (via N-terminus) with KCNMB4 (By similarity). Interacts with KCNT1 (via C-terminus); this interaction alters gating properties of KCNT1 (PubMed:20512134). Interacts (via C-terminus) with KIF5A; this interaction is increased in a mGluR-dependent manner (By similarity). Interacts (via phosphorylated form) with MCRS1 (via N-terminus) (By similarity). Interacts with MOV10; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs (By similarity). Interacts with MYO5A and PURA; these interactions occur in association with polyribosome (By similarity). Interacts with NCL (By similarity). Interacts with NUFIP1 (By similarity). Interacts (via N-terminus) with NUFIP2 (By similarity). Interacts with NXF1; this interaction occurs in a mRNA-dependent and polyribosome-independent manner in the nucleus (By similarity). Interacts with NXF2 (via N-terminus); this interaction is direct and occurs in a NXF1 mRNA-containing mRNP complexes (By similarity). Interacts with RANBP9; this interaction is direct and inhibits binding of FMR1 to RNA homopolymer (By similarity). Interacts with RPLP0 (By similarity). Interacts (via C-terminus) with SMN (via C-terminus); this interaction is direct and occurs in a RNA-independent manner (By similarity). Interacts with TDRD3 (via C-terminus); this interaction is direct (By similarity). Interacts with YBX1; this interaction occurs in association with polyribosome (By similarity). Interacts with nucleosome (By similarity). Associates with polyribosome; this association occurs in a mRNA-dependent manner (PubMed:9030614, PubMed:9144248, PubMed:14613971, PubMed:16571602). Associates with messenger ribonucleoprotein particles (mRNPs) (PubMed:16571602). Associates with microtubules in a kinesin- and dynein-dependent manner (By similarity). Interacts with HABP4 (By similarity).By similarity6 Publications

GO - Molecular functioni

  • methylated histone binding Source: UniProtKB
  • microtubule binding Source: UniProtKB
  • protein domain specific binding Source: RGD
  • protein heterodimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • protein kinase binding Source: RGD
  • protein phosphatase binding Source: RGD

Protein-protein interaction databases

BioGridi247050, 1 interactor
IntActiQ80WE1, 1 interactor


3D structure databases


Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 50Agenet-like 1PROSITE-ProRule annotationAdd BLAST47
Domaini63 – 115Agenet-like 2PROSITE-ProRule annotationAdd BLAST53
Domaini218 – 279KH 1PROSITE-ProRule annotationAdd BLAST62
Domaini281 – 348KH 2PROSITE-ProRule annotationAdd BLAST68


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 184Required for nuclear localizationBy similarityAdd BLAST184
Regioni172 – 211Necessary for interaction with CYFIP1, CYFIP2, FXR1 and FXR2By similarityAdd BLAST40
Regioni375 – 469Required for nuclear exportBy similarityAdd BLAST95
Regioni397 – 593Interaction with RANBP9By similarityAdd BLAST197
Regioni512 – 526RNA-binding RGG-boxBy similarityAdd BLAST15


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi402 – 421Nuclear export signalBy similarityAdd BLAST20
Motifi505 – 512Nucleolar localization signal 1By similarity8
Motifi574 – 578Nucleolar localization signal 2By similarity5


The N-terminal 134 amino acids are necessary for homodimerization and RNA-binding. The N-terminal 298 amino acids are sufficient to interact with KCNMB4 and to regulate presynaptic action potential (AP) duration in neurons. The two agenet-like domains are necessary for binding to histone H3 in a methylation-dependent manner. The KH domains are necessary for mediating miRNA annealing to specific RNA targets. The KH 2 domain is necessary for binding to kissing complex (kc) RNA ligands. The RGG box domain is necessary for binding to mRNA targets that contain G-quadruplex structures. The RGG-box domain is necessary for binding to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the superoxide dismutase SOD1 mRNA. The RGG box domain is necessary for binding to its own mRNA. The RGG-box domain is necessary for binding to homopolymer poly(G).By similarity

Sequence similaritiesi

Belongs to the FMR1 family.Curated

Keywords - Domaini


Phylogenomic databases

eggNOGiENOG410IF9J Eukaryota

Family and domain databases

Gene3Di3.30.1370.10, 1 hit
InterProiView protein in InterPro
IPR008395 Agenet-like_dom
IPR032196 FXMR_C2
IPR022034 FXMRP1_C_core
IPR004087 KH_dom
IPR004088 KH_dom_type_1
IPR036612 KH_dom_type_1_sf
PfamiView protein in Pfam
PF05641 Agenet, 1 hit
PF16098 FXMR_C2, 2 hits
PF12235 FXMRP1_C_core, 1 hit
PF00013 KH_1, 2 hits
SMARTiView protein in SMART
SM00322 KH, 2 hits
SUPFAMiSSF54791 SSF54791, 2 hits
PROSITEiView protein in PROSITE
PS51641 AGENET_LIKE, 2 hits
PS50084 KH_TYPE_1, 2 hits

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q80WE1-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

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Mass (Da):66,780
Last modified:July 1, 2008 - v2
Isoform 2 (identifier: Q80WE1-2) [UniParc]FASTAAdd to basket
Also known as: 18

The sequence of this isoform differs from the canonical sequence as follows:
     469-480: Missing.

Show »
Mass (Da):65,631

Sequence cautioni

The sequence AAB07073 differs from that shown. N-ter sequencing errors.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti110E → D in AAB07073 (Ref. 2) Curated1
Sequence conflicti184L → S in AAB07073 (Ref. 2) Curated1
Sequence conflicti424A → V in AAB07073 (Ref. 2) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_034393469 – 480Missing in isoform 2. 1 PublicationAdd BLAST12

Sequence databases

Select the link destinations:
Links Updated
AY240947 mRNA Translation: AAP15341.1
U60145 mRNA Translation: AAB07073.1 Sequence problems.
RefSeqiNP_434691.1, NM_052804.1 [Q80WE1-2]
XP_006229594.1, XM_006229532.3 [Q80WE1-1]

Genome annotation databases

EnsembliENSRNOT00000087893; ENSRNOP00000074033; ENSRNOG00000057464 [Q80WE1-2]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiFMR1_RAT
AccessioniPrimary (citable) accession number: Q80WE1
Secondary accession number(s): P70568
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 2008
Last sequence update: July 1, 2008
Last modified: June 20, 2018
This is version 112 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Reference proteome

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