FRG1_HUMAN
ID FRG1_HUMAN Reviewed; 258 AA.
AC Q14331; A8K775;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 177.
DE RecName: Full=Protein FRG1 {ECO:0000305};
DE AltName: Full=FSHD region gene 1 protein;
GN Name=FRG1 {ECO:0000312|HGNC:HGNC:3954};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8733123; DOI=10.1093/hmg/5.5.581;
RA van Deutekom J.C.T., Lemmers R.J.L.F., Grewal P.K., van Geel M.,
RA Romberg S., Dauwerse H.G., Wright T.J., Padberg G.W., Hofker M.H.,
RA Hewitt J.E., Frants R.R.;
RT "Identification of the first gene (FRG1) from the FSHD region on human
RT chromosome 4q35.";
RL Hum. Mol. Genet. 5:581-590(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10512680; DOI=10.1006/geno.1999.5942;
RA van Geel M., Heather L.J., Lyle R., Hewitt J.E., Frants R.R., de Jong P.J.;
RT "The FSHD region on human chromosome 4q35 contains potential coding regions
RT among pseudogenes and a high density of repeat elements.";
RL Genomics 61:55-65(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, IDENTIFICATION BY MASS SPECTROMETRY, AND IDENTIFICATION IN THE
RP SPLICEOSOMAL C COMPLEX.
RX PubMed=11991638; DOI=10.1017/s1355838202021088;
RA Jurica M.S., Licklider L.J., Gygi S.P., Grigorieff N., Moore M.J.;
RT "Purification and characterization of native spliceosomes suitable for
RT three-dimensional structural analysis.";
RL RNA 8:426-439(2002).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15060122; DOI=10.1136/jmg2003.012781;
RA van Koningsbruggen S., Dirks R.W., Mommaas A.M., Onderwater J.J.,
RA Deidda G., Padberg G.W., Frants R.R., van der Maarel S.M.;
RT "FRG1P is localised in the nucleolus, Cajal bodies, and speckles.";
RL J. Med. Genet. 41:E46-E46(2004).
RN [8]
RP OVEREXPRESSION, AND INVOLVEMENT IN FSHD1.
RX PubMed=16341202; DOI=10.1038/nature04422;
RA Gabellini D., D'Antona G., Moggio M., Prelle A., Zecca C., Adami R.,
RA Angeletti B., Ciscato P., Pellegrino M.A., Bottinelli R., Green M.R.,
RA Tupler R.;
RT "Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1.";
RL Nature 439:973-977(2006).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH GARIN3; SMN1 AND
RP PABPN1.
RX PubMed=17103222; DOI=10.1007/s00412-006-0083-3;
RA van Koningsbruggen S., Straasheijm K.R., Sterrenburg E., de Graaf N.,
RA Dauwerse H.G., Frants R.R., van der Maarel S.M.;
RT "FRG1P-mediated aggregation of proteins involved in pre-mRNA processing.";
RL Chromosoma 116:53-64(2007).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=20970242; DOI=10.1016/j.diff.2010.09.185;
RA Hanel M.L., Sun C.Y., Jones T.I., Long S.W., Zanotti S., Milner D.,
RA Jones P.L.;
RT "Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a
RT dynamic nuclear and sarcomeric protein.";
RL Differentiation 81:107-118(2011).
RN [12]
RP FUNCTION, HOMODIMERIZATION, HOMOTETRAMERIZATION, INTERACTION WITH KPNA2 AND
RP NXF1, RNA-BINDING, ACTIN-BINDING, SUBCELLULAR LOCATION, AND NUCLEAR
RP LOCALIZATION SIGNAL.
RX PubMed=21699900; DOI=10.1016/j.jmb.2011.06.014;
RA Sun C.Y., van Koningsbruggen S., Long S.W., Straasheijm K., Klooster R.,
RA Jones T.I., Bellini M., Levesque L., Brieher W.M., van der Maarel S.M.,
RA Jones P.L.;
RT "Facioscapulohumeral muscular dystrophy region gene 1 is a dynamic RNA-
RT associated and actin-bundling protein.";
RL J. Mol. Biol. 411:397-416(2011).
RN [13]
RP FUNCTION, OVEREXPRESSION, SUBCELLULAR LOCATION, INTERACTION WITH KMT5B, AND
RP INVOLVEMENT IN FSHD1.
RX PubMed=23720823; DOI=10.1093/jmcb/mjt018;
RA Neguembor M.V., Xynos A., Onorati M.C., Caccia R., Bortolanza S., Godio C.,
RA Pistoni M., Corona D.F., Schotta G., Gabellini D.;
RT "FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone
RT methyltransferase and impairs myogenesis.";
RL J. Mol. Cell Biol. 5:294-307(2013).
CC -!- FUNCTION: Binds to mRNA in a sequence-independent manner. May play a
CC role in regulation of pre-mRNA splicing or in the assembly of rRNA into
CC ribosomal subunits. May be involved in mRNA transport. May be involved
CC in epigenetic regulation of muscle differentiation through regulation
CC of activity of the histone-lysine N-methyltransferase KMT5B.
CC {ECO:0000269|PubMed:11991638, ECO:0000269|PubMed:15060122,
CC ECO:0000269|PubMed:20970242, ECO:0000269|PubMed:21699900,
CC ECO:0000269|PubMed:23720823}.
CC -!- SUBUNIT: Homodimer and homotetramer in solution. Identified in the
CC spliceosome C complex. Interacts with KMT5B (via C-terminus). Interacts
CC (via N-terminus) with KPNA2 and NXF1/TAP. Interacts with F-actin with a
CC stoichiometry of 2:1. Interacts with GARIN3, SMN1 and PABPN1
CC (PubMed:17103222). {ECO:0000269|PubMed:11991638,
CC ECO:0000269|PubMed:17103222, ECO:0000269|PubMed:21699900,
CC ECO:0000269|PubMed:23720823}.
CC -!- INTERACTION:
CC Q14331; Q9HCG8: CWC22; NbExp=2; IntAct=EBI-2515248, EBI-373289;
CC Q14331; Q96B26: EXOSC8; NbExp=3; IntAct=EBI-2515248, EBI-371922;
CC Q14331; Q14749: GNMT; NbExp=3; IntAct=EBI-2515248, EBI-744239;
CC Q14331; Q6A162: KRT40; NbExp=3; IntAct=EBI-2515248, EBI-10171697;
CC Q14331; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-2515248, EBI-741037;
CC -!- SUBCELLULAR LOCATION: Nucleus, Cajal body {ECO:0000269|PubMed:15060122,
CC ECO:0000269|PubMed:17103222, ECO:0000269|PubMed:21699900}. Nucleus,
CC nucleolus {ECO:0000269|PubMed:15060122, ECO:0000269|PubMed:20970242,
CC ECO:0000269|PubMed:21699900}. Cytoplasm {ECO:0000269|PubMed:20970242,
CC ECO:0000269|PubMed:21699900}. Cytoplasm, myofibril, sarcomere, Z line
CC {ECO:0000269|PubMed:20970242}. Note=Localization changes during
CC myogenesis from mainly cytoplasmic in undifferentiated myoblasts, to
CC strongly nucleolar in early myotubes and back to cytoplasmic 5 days
CC post-differentiation (PubMed:20970242). Localized at the Z-line in the
CC sarcomere of matured myotubes 8 days post-differentiation
CC (PubMed:20970242). {ECO:0000269|PubMed:20970242}.
CC -!- TISSUE SPECIFICITY: Expressed in adult muscle, lymphocytes, fetal
CC brain, muscle, and placenta. Also expressed in the smooth muscle of
CC arteries and veins, the sweat glands and the epidermis.
CC {ECO:0000269|PubMed:20970242}.
CC -!- DISEASE: Facioscapulohumeral muscular dystrophy 1 (FSHD1) [MIM:158900]:
CC A degenerative muscle disease characterized by slowly progressive
CC weakness of the muscles of the face, upper-arm, and shoulder girdle.
CC The onset of symptoms usually occurs in the first or second decade of
CC life. Affected individuals usually present with impairment of upper
CC extremity elevation. This tends to be followed by facial weakness,
CC primarily involving the orbicularis oris and orbicularis oculi muscles.
CC {ECO:0000269|PubMed:16341202, ECO:0000269|PubMed:23720823}. Note=The
CC gene represented in this entry may be involved in disease pathogenesis.
CC Overexpression of human FRG1 in mice leads to development of
CC facioscapulohumeral muscular dystrophy (FSHD1)-like symptoms such as
CC kyphosis, progressive muscle dystrophy and skeletal muscle atrophy
CC (PubMed:16341202). It also causes aberrant pre-mRNA splicing of TNNT3
CC and MTMR1, affects the localization and activity of KMT5B, and leads to
CC increased levels of EID3, resulting in inhibited muscle differentiation
CC (PubMed:23720823). These results suggest that FSHD1 results from
CC inappropriate overexpression of FRG1 which leads to abnormal
CC alternative splicing of specific pre-mRNAs.
CC {ECO:0000269|PubMed:16341202, ECO:0000269|PubMed:23720823}.
CC -!- SIMILARITY: Belongs to the FRG1 family. {ECO:0000305}.
CC -!- CAUTION: Was originally thought to be located in nuclear speckles based
CC on overexpression of the protein (PubMed:15060122). However, the
CC endogenous protein was later shown not be expressed in nuclear speckles
CC (PubMed:21699900). {ECO:0000305|PubMed:15060122,
CC ECO:0000305|PubMed:21699900}.
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DR EMBL; L76159; AAA95939.1; -; mRNA.
DR EMBL; AF146191; AAD46768.1; -; Genomic_DNA.
DR EMBL; AK291890; BAF84579.1; -; mRNA.
DR EMBL; CH471056; EAX04600.1; -; Genomic_DNA.
DR EMBL; BC053997; AAH53997.1; -; mRNA.
DR CCDS; CCDS34121.1; -.
DR RefSeq; NP_004468.1; NM_004477.2.
DR PDB; 6ZYM; EM; 3.40 A; x=1-258.
DR PDB; 7A5P; EM; 5.00 A; x=1-258.
DR PDBsum; 6ZYM; -.
DR PDBsum; 7A5P; -.
DR AlphaFoldDB; Q14331; -.
DR SMR; Q14331; -.
DR BioGRID; 108764; 34.
DR CORUM; Q14331; -.
DR IntAct; Q14331; 16.
DR MINT; Q14331; -.
DR STRING; 9606.ENSP00000226798; -.
DR GlyGen; Q14331; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q14331; -.
DR PhosphoSitePlus; Q14331; -.
DR SwissPalm; Q14331; -.
DR BioMuta; FRG1; -.
DR DMDM; 18202499; -.
DR EPD; Q14331; -.
DR jPOST; Q14331; -.
DR MassIVE; Q14331; -.
DR MaxQB; Q14331; -.
DR PaxDb; Q14331; -.
DR PeptideAtlas; Q14331; -.
DR PRIDE; Q14331; -.
DR ProteomicsDB; 59967; -.
DR Antibodypedia; 29157; 218 antibodies from 25 providers.
DR DNASU; 2483; -.
DR Ensembl; ENST00000226798.9; ENSP00000226798.4; ENSG00000109536.12.
DR Ensembl; ENST00000620886.3; ENSP00000483471.1; ENSG00000275145.3.
DR Ensembl; ENST00000636590.2; ENSP00000490541.1; ENSG00000283153.2.
DR Ensembl; ENST00000637998.2; ENSP00000489690.1; ENSG00000283630.2.
DR GeneID; 2483; -.
DR KEGG; hsa:2483; -.
DR MANE-Select; ENST00000226798.9; ENSP00000226798.4; NM_004477.3; NP_004468.1.
DR UCSC; uc003izs.4; human.
DR CTD; 2483; -.
DR DisGeNET; 2483; -.
DR GeneCards; FRG1; -.
DR GeneReviews; FRG1; -.
DR HGNC; HGNC:3954; FRG1.
DR HPA; ENSG00000109536; Low tissue specificity.
DR MalaCards; FRG1; -.
DR MIM; 158900; phenotype.
DR MIM; 601278; gene.
DR neXtProt; NX_Q14331; -.
DR OpenTargets; ENSG00000109536; -.
DR Orphanet; 269; Facioscapulohumeral dystrophy.
DR PharmGKB; PA28372; -.
DR VEuPathDB; HostDB:ENSG00000109536; -.
DR eggNOG; KOG3962; Eukaryota.
DR GeneTree; ENSGT00390000004552; -.
DR HOGENOM; CLU_094616_0_0_1; -.
DR InParanoid; Q14331; -.
DR OMA; EQWEPIF; -.
DR OrthoDB; 390511at2759; -.
DR PhylomeDB; Q14331; -.
DR TreeFam; TF314108; -.
DR PathwayCommons; Q14331; -.
DR SignaLink; Q14331; -.
DR SIGNOR; Q14331; -.
DR BioGRID-ORCS; 2483; 66 hits in 1009 CRISPR screens.
DR ChiTaRS; FRG1; human.
DR GeneWiki; FRG1; -.
DR GenomeRNAi; 2483; -.
DR Pharos; Q14331; Tbio.
DR PRO; PR:Q14331; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q14331; protein.
DR Bgee; ENSG00000109536; Expressed in calcaneal tendon and 100 other tissues.
DR ExpressionAtlas; Q14331; baseline and differential.
DR Genevisible; Q14331; HS.
DR GO; GO:0015030; C:Cajal body; IEA:UniProtKB-SubCell.
DR GO; GO:0071013; C:catalytic step 2 spliceosome; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IBA:GO_Central.
DR GO; GO:0055120; C:striated muscle dense body; IBA:GO_Central.
DR GO; GO:0030018; C:Z disc; IEA:UniProtKB-SubCell.
DR GO; GO:0051015; F:actin filament binding; IBA:GO_Central.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IC:UniProtKB.
DR GO; GO:0007517; P:muscle organ development; IEA:UniProtKB-KW.
DR GO; GO:0006364; P:rRNA processing; IEA:UniProtKB-KW.
DR InterPro; IPR008999; Actin-crosslinking.
DR InterPro; IPR010414; FRG1.
DR PANTHER; PTHR12928; PTHR12928; 1.
DR Pfam; PF06229; FRG1; 1.
DR SUPFAM; SSF50405; SSF50405; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Actin-binding; Cytoplasm; mRNA processing; mRNA splicing;
KW Myogenesis; Nucleus; Reference proteome; Ribosome biogenesis; RNA-binding;
KW rRNA processing; Spliceosome.
FT CHAIN 1..258
FT /note="Protein FRG1"
FT /id="PRO_0000220767"
FT MOTIF 22..32
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 235..251
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000255"
FT VARIANT 19
FT /note="T -> A (in dbSNP:rs17797703)"
FT /id="VAR_049105"
FT HELIX 232..237
FT /evidence="ECO:0007829|PDB:6ZYM"
FT HELIX 240..248
FT /evidence="ECO:0007829|PDB:6ZYM"
FT TURN 255..257
FT /evidence="ECO:0007829|PDB:6ZYM"
SQ SEQUENCE 258 AA; 29172 MW; FFBC981B7602BDB3 CRC64;
MAEYSYVKST KLVLKGTKTK SKKKKSKDKK RKREEDEETQ LDIVGIWWTV TNFGEISGTI
AIEMDKGTYI HALDNGLFTL GAPHKEVDEG PSPPEQFTAV KLSDSRIALK SGYGKYLGIN
SDGLVVGRSD AIGPREQWEP VFQNGKMALL ASNSCFIRCN EAGDIEAKSK TAGEEEMIKI
RSCAERETKK KDDIPEEDKG NVKQCEINYV KKFQSFQDHK LKISKEDSKI LKKARKDGFL
HETLLDRRAK LKADRYCK