FNDC5_HUMAN
ID FNDC5_HUMAN Reviewed; 212 AA.
AC Q8NAU1; A6NMC9; D3DPQ6; Q6P6D9; Q7Z676;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2012, sequence version 3.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Fibronectin type III domain-containing protein 5;
DE AltName: Full=Fibronectin type III repeat-containing protein 2;
DE Contains:
DE RecName: Full=Irisin;
DE Flags: Precursor;
GN Name=FNDC5; Synonyms=FRCP2;
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 [LARGE SCALE MRNA] (ISOFORM 4).
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-133 (ISOFORM 1).
RG The Cancer Genome Anatomy Project (CGAP) at the National Cancer Institute;
RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 20-212 (ISOFORM 2).
RC TISSUE=Fetal liver;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=22237023; DOI=10.1038/nature10777;
RA Bostrom P., Wu J., Jedrychowski M.P., Korde A., Ye L., Lo J.C.,
RA Rasbach K.A., Bostrom E.A., Choi J.H., Long J.Z., Kajimura S.,
RA Zingaretti M.C., Vind B.F., Tu H., Cinti S., Hojlund K., Gygi S.P.,
RA Spiegelman B.M.;
RT "A PGC1-alpha-dependent myokine that drives brown-fat-like development of
RT white fat and thermogenesis.";
RL Nature 481:463-468(2012).
RN [8]
RP FUNCTION, INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=24040023; DOI=10.1371/journal.pone.0073680;
RA Raschke S., Elsen M., Gassenhuber H., Sommerfeld M., Schwahn U.,
RA Brockmann B., Jung R., Wisloff U., Tjonna A.E., Raastad T., Hallen J.,
RA Norheim F., Drevon C.A., Romacho T., Eckardt K., Eckel J.;
RT "Evidence against a Beneficial Effect of Irisin in Humans.";
RL PLoS ONE 8:E73680-E73680(2013).
CC -!- FUNCTION: [Irisin]: Contrary to mouse, may not be involved in the
CC beneficial effects of muscular exercise, nor in the induction of
CC browning of human white adipose tissue. {ECO:0000269|PubMed:24040023}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22237023};
CC Single-pass type I membrane protein {ECO:0000269|PubMed:22237023}.
CC Peroxisome membrane {ECO:0000250}; Single-pass type I membrane protein
CC {ECO:0000250}. Note=Imported in peroxisomes through the PEX5 receptor
CC pathway. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [Irisin]: Secreted. Note=Detected in the blood of
CC individuals subjected to endurance exercise.
CC {ECO:0000269|PubMed:22237023}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q8NAU1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8NAU1-2; Sequence=VSP_032861, VSP_032862;
CC Name=3;
CC IsoId=Q8NAU1-3; Sequence=VSP_032860, VSP_032863;
CC Name=4;
CC IsoId=Q8NAU1-4; Sequence=VSP_032860;
CC -!- TISSUE SPECIFICITY: Widely expressed, with highest levels in heart.
CC Very low expression, if any, in colon, pancreas and spleen.
CC {ECO:0000269|PubMed:24040023}.
CC -!- INDUCTION: Has been shown to be up-regulated some twofold by muscular
CC exercise at the mRNA and protein level; this effect has been suggested
CC to be mediated by PPARGC1A (PubMed:22237023). However, up-regulation
CC upon exercise could not be reproduced, at least not at the mRNA level
CC (PubMed:24040023). {ECO:0000269|PubMed:22237023,
CC ECO:0000269|PubMed:24040023}.
CC -!- PTM: The extracellular domain is cleaved and released from the cell
CC membrane.
CC -!- PTM: N-Glycosylated. {ECO:0000250}.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-76 is the initiator.
CC Transcript evidence available at present time points at Met-76. In this
CC short version of the protein, the signal peptide cannot be predicted
CC and the irisin peptide is severely truncated. The first initiation
CC codon corresponds to a non-AUG site, an N-terminal ATA codon. This
CC initiation codon has been annotated as it is in good Kozak context and
CC it is conserved in other primates, including gibbon, chimpanzee and
CC gorilla. Although the existence of such a form has not been
CC demonstrated in human, western blot analysis following endurance
CC exercise shows the presence of an irisin peptide of similar size in
CC human and mouse plasma (PubMed:22237023), suggesting the existence of
CC full-length irisin in human, at least in some tissues. However,
CC expression from Met-1 may be less efficient than that from Met-76
CC (PubMed:24040023). {ECO:0000305|PubMed:22237023,
CC ECO:0000305|PubMed:24040023}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AK092102; BAC03806.1; -; mRNA.
DR EMBL; AC114493; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471059; EAX07499.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07502.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07500.1; -; Genomic_DNA.
DR EMBL; BC062297; AAH62297.1; -; mRNA.
DR EMBL; BX537781; CAD97840.1; -; mRNA.
DR EMBL; BF221649; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS369.2; -. [Q8NAU1-1]
DR CCDS; CCDS65483.1; -. [Q8NAU1-3]
DR RefSeq; NP_001165411.2; NM_001171940.1. [Q8NAU1-2]
DR RefSeq; NP_001165412.1; NM_001171941.2. [Q8NAU1-3]
DR RefSeq; NP_715637.2; NM_153756.2. [Q8NAU1-1]
DR PDB; 4LSD; X-ray; 2.28 A; A/B/C/D/E/F/G/H=33-130.
DR PDBsum; 4LSD; -.
DR AlphaFoldDB; Q8NAU1; -.
DR SMR; Q8NAU1; -.
DR BioGRID; 128948; 148.
DR IntAct; Q8NAU1; 8.
DR STRING; 9606.ENSP00000362570; -.
DR GlyGen; Q8NAU1; 2 sites.
DR iPTMnet; Q8NAU1; -.
DR PhosphoSitePlus; Q8NAU1; -.
DR BioMuta; FNDC5; -.
DR DMDM; 403314395; -.
DR jPOST; Q8NAU1; -.
DR MassIVE; Q8NAU1; -.
DR PaxDb; Q8NAU1; -.
DR PeptideAtlas; Q8NAU1; -.
DR PRIDE; Q8NAU1; -.
DR ProteomicsDB; 72700; -. [Q8NAU1-1]
DR ProteomicsDB; 72701; -. [Q8NAU1-2]
DR ProteomicsDB; 72702; -. [Q8NAU1-3]
DR ProteomicsDB; 72703; -. [Q8NAU1-4]
DR Antibodypedia; 54866; 207 antibodies from 28 providers.
DR DNASU; 252995; -.
DR Ensembl; ENST00000373471.9; ENSP00000362570.5; ENSG00000160097.20. [Q8NAU1-1]
DR Ensembl; ENST00000496770.1; ENSP00000476320.1; ENSG00000160097.20. [Q8NAU1-3]
DR GeneID; 252995; -.
DR KEGG; hsa:252995; -.
DR MANE-Select; ENST00000373471.9; ENSP00000362570.5; NM_153756.3; NP_715637.2.
DR UCSC; uc001bwg.5; human. [Q8NAU1-1]
DR CTD; 252995; -.
DR DisGeNET; 252995; -.
DR GeneCards; FNDC5; -.
DR HGNC; HGNC:20240; FNDC5.
DR HPA; ENSG00000160097; Group enriched (skeletal muscle, tongue).
DR MIM; 611906; gene.
DR neXtProt; NX_Q8NAU1; -.
DR OpenTargets; ENSG00000160097; -.
DR PharmGKB; PA134924607; -.
DR VEuPathDB; HostDB:ENSG00000160097; -.
DR eggNOG; ENOG502QQCU; Eukaryota.
DR GeneTree; ENSGT00390000004923; -.
DR HOGENOM; CLU_089166_2_0_1; -.
DR InParanoid; Q8NAU1; -.
DR OMA; TTHSCAL; -.
DR OrthoDB; 1198350at2759; -.
DR TreeFam; TF325415; -.
DR PathwayCommons; Q8NAU1; -.
DR SignaLink; Q8NAU1; -.
DR BioGRID-ORCS; 252995; 4 hits in 919 CRISPR screens.
DR ChiTaRS; FNDC5; human.
DR GenomeRNAi; 252995; -.
DR Pharos; Q8NAU1; Tbio.
DR PRO; PR:Q8NAU1; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q8NAU1; protein.
DR Bgee; ENSG00000160097; Expressed in skeletal muscle tissue of biceps brachii and 140 other tissues.
DR ExpressionAtlas; Q8NAU1; baseline and differential.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005778; C:peroxisomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005179; F:hormone activity; IEA:UniProtKB-KW.
DR GO; GO:0090336; P:positive regulation of brown fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0014850; P:response to muscle activity; ISS:UniProtKB.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR032073; FNDC5_C.
DR InterPro; IPR013783; Ig-like_fold.
DR Pfam; PF16066; DUF4808; 1.
DR Pfam; PF00041; fn3; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR PROSITE; PS50853; FN3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Glycoprotein; Hormone;
KW Membrane; Peroxisome; Reference proteome; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..31
FT /evidence="ECO:0000255"
FT CHAIN 32..212
FT /note="Fibronectin type III domain-containing protein 5"
FT /id="PRO_0000328971"
FT CHAIN 32..143
FT /note="Irisin"
FT /id="PRO_0000415857"
FT TOPO_DOM 32..152
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 153..173
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 174..212
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 36..127
FT /note="Fibronectin type-III"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 182..212
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 210..212
FT /note="Microbody targeting signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 182..196
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 39
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 84
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..75
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_032860"
FT VAR_SEQ 180..181
FT /note="KD -> EA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_032861"
FT VAR_SEQ 182..212
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_032862"
FT VAR_SEQ 212
FT /note="I -> VRARPGPGWATLCLMLW (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_032863"
FT STRAND 38..44
FT /evidence="ECO:0007829|PDB:4LSD"
FT STRAND 50..55
FT /evidence="ECO:0007829|PDB:4LSD"
FT TURN 59..61
FT /evidence="ECO:0007829|PDB:4LSD"
FT STRAND 62..73
FT /evidence="ECO:0007829|PDB:4LSD"
FT STRAND 77..84
FT /evidence="ECO:0007829|PDB:4LSD"
FT STRAND 89..92
FT /evidence="ECO:0007829|PDB:4LSD"
FT STRAND 100..111
FT /evidence="ECO:0007829|PDB:4LSD"
FT STRAND 120..123
FT /evidence="ECO:0007829|PDB:4LSD"
SQ SEQUENCE 212 AA; 23659 MW; C4A066452A05A134 CRC64;
MHPGSPSAWP PRARAALRLW LGCVCFALVQ ADSPSAPVNV TVRHLKANSA VVSWDVLEDE
VVIGFAISQQ KKDVRMLRFI QEVNTTTRSC ALWDLEEDTE YIVHVQAISI QGQSPASEPV
LFKTPREAEK MASKNKDEVT MKEMGRNQQL RTGEVLIIVV VLFMWAGVIA LFCRQYDIIK
DNEPNNNKEK TKSASETSTP EHQGGGLLRS KI
