ID FBXL5_HUMAN Reviewed; 691 AA. AC Q9UKA1; A8MSK4; B4DIB5; Q4W5A8; Q8NHP3; Q9NXN2; Q9P0I0; Q9P0X5; Q9UJT7; AC Q9UKC8; DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 03-OCT-2003, sequence version 2. DT 10-JUN-2026, entry version 203. DE RecName: Full=F-box/LRR-repeat protein 5; DE AltName: Full=F-box and leucine-rich repeat protein 5; DE AltName: Full=F-box protein FBL4/FBL5; DE AltName: Full=p45SKP2-like protein; GN Name=FBXL5; Synonyms=FBL4, FBL5, FLR1; 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] (ISOFORM 1). RX PubMed=10531037; DOI=10.1016/s0960-9822(00)80021-4; RA Winston J.T., Koepp D.M., Zhu C., Elledge S.J., Harper J.W.; RT "A family of mammalian F-box proteins."; RL Curr. Biol. 9:1180-1182(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=10945468; DOI=10.1006/geno.2000.6211; RA Ilyin G.P., Rialland M., Pigeon C., Guguen-Guillouzo C.; RT "cDNA cloning and expression analysis of new members of the mammalian F-box RT protein family."; RL Genomics 67:40-47(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Shimbara N.; RT "cDNA cloning of a new human protein, FLR1, containing both motifs of F-box RT and leucine-rich repeat."; RL Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 56-691 (ISOFORMS 1/2). RC TISSUE=Colon, and Hippocampus; 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Cervix; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [7] 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-691 (ISOFORM 1). RC TISSUE=Adrenal gland; RA Huang C., Zhang C., Wu T., Peng Y., Gu Y., Jin Y., Jiang C., Li Y., Han Z., RA Wang Y., Chen Z., Fu G.; RT "A novel gene expressed in the human adrenal gland."; RL Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 157-691 (ISOFORMS 1/2). RX PubMed=10531035; DOI=10.1016/s0960-9822(00)80020-2; RA Cenciarelli C., Chiaur D.S., Guardavaccaro D., Parks W., Vidal M., RA Pagano M.; RT "Identification of a family of human F-box proteins."; RL Curr. Biol. 9:1177-1179(1999). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH DCTN1. RX PubMed=17532294; DOI=10.1016/j.bbrc.2007.05.068; RA Zhang N., Liu J., Ding X., Aikhionbare F., Jin C., Yao X.; RT "FBXL5 interacts with p150Glued and regulates its ubiquitination."; RL Biochem. Biophys. Res. Commun. 359:34-39(2007). RN [12] RP FUNCTION, INTERACTION WITH ACO1 AND IREB2, IDENTIFICATION IN A SCF PROTEIN RP LIGASE COMPLEX, IRON-BINDING, DOMAIN HEMERYTHRIN-LIKE, UBIQUITINATION, AND RP MUTAGENESIS OF HIS-15 AND HIS-57. RX PubMed=19762596; DOI=10.1126/science.1176333; RA Vashisht A.A., Zumbrennen K.B., Huang X., Powers D.N., Durazo A., Sun D., RA Bhaskaran N., Persson A., Uhlen M., Sangfelt O., Spruck C., Leibold E.A., RA Wohlschlegel J.A.; RT "Control of iron homeostasis by an iron-regulated ubiquitin ligase."; RL Science 326:718-721(2009). RN [13] RP FUNCTION, INTERACTION WITH ACO1 AND IREB2, IDENTIFICATION IN A SCF PROTEIN RP LIGASE COMPLEX, IRON-BINDING, DOMAIN HEMERYTHRIN-LIKE, UBIQUITINATION, AND RP MUTAGENESIS OF HIS-57 AND GLU-61. RX PubMed=19762597; DOI=10.1126/science.1176326; RA Salahudeen A.A., Thompson J.W., Ruiz J.C., Ma H.-W., Kinch L.N., Li Q., RA Grishin N.V., Bruick R.K.; RT "An E3 ligase possessing an iron responsive hemerythrin domain is a RT regulator of iron homeostasis."; RL Science 326:722-726(2009). RN [14] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24157836; DOI=10.1093/nar/gkt935; RA Vinas-Castells R., Frias A., Robles-Lanuza E., Zhang K., Longmore G.D., RA Garcia de Herreros A., Diaz V.M.; RT "Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and RT stability."; RL Nucleic Acids Res. 42:1079-1094(2014). RN [15] RP UBIQUITINATION BY HERC2. RX PubMed=24778179; DOI=10.1074/jbc.m113.541490; RA Moroishi T., Yamauchi T., Nishiyama M., Nakayama K.I.; RT "HERC2 targets the iron regulator FBXL5 for degradation and modulates iron RT metabolism."; RL J. Biol. Chem. 289:16430-16441(2014). RN [16] RP FUNCTION. RX PubMed=25249620; DOI=10.1093/nar/gku876; RA Chen Z.W., Liu B., Tang N.W., Xu Y.H., Ye X.Y., Li Z.M., Niu X.M., RA Shen S.P., Lu S., Xu L.; RT "FBXL5-mediated degradation of single-stranded DNA-binding protein hSSB1 RT controls DNA damage response."; RL Nucleic Acids Res. 42:11560-11569(2014). RN [17] RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-160, IRON-BINDING, AND RP MISCELLANEOUS. RX PubMed=22492618; DOI=10.1002/cbic.201200043; RA Shu C., Sung M.W., Stewart M.D., Igumenova T.I., Tan X., Li P.; RT "The structural basis of iron sensing by the human F-box protein FBXL5."; RL ChemBioChem 13:788-791(2012). RN [18] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 1-161, AND IRON-BINDING. RX PubMed=22253436; DOI=10.1074/jbc.m111.308684; RA Thompson J.W., Salahudeen A.A., Chollangi S., Ruiz J.C., Brautigam C.A., RA Makris T.M., Lipscomb J.D., Tomchick D.R., Bruick R.K.; RT "Structural and molecular characterization of iron-sensing hemerythrin-like RT domain within F-box and leucine-rich repeat protein 5 (FBXL5)."; RL J. Biol. Chem. 287:7357-7365(2012). RN [19] {ECO:0007744|PDB:6VCD} RP STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) OF 200-691 IN COMPLEX RP WITH [2FE-2S] CLUSTER, FUNCTION, COFACTOR, ACTIVITY REGULATION, AND RP MUTAGENESIS OF CYS-662; CYS-676; CYS-686 AND CYS-687. RX PubMed=32126207; DOI=10.1016/j.molcel.2020.02.011; RA Wang H., Shi H., Rajan M., Canarie E.R., Hong S., Simoneschi D., Pagano M., RA Bush M.F., Stoll S., Leibold E.A., Zheng N.; RT "FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen- RT Responsive [2Fe2S] Cluster."; RL Mol. Cell 78:31-41(2020). CC -!- FUNCTION: Component of some SCF (SKP1-cullin-F-box) protein ligase CC complex that plays a central role in iron homeostasis by promoting the CC ubiquitination and subsequent degradation of IREB2/IRP2 CC (PubMed:19762596, PubMed:19762597). The C-terminal domain of FBXL5 CC contains a redox-sensitive [2Fe-2S] cluster that, upon oxidation, CC promotes binding to IRP2 to effect its oxygen-dependent degradation CC (PubMed:32126207). Under iron deficiency conditions, the N-terminal CC hemerythrin-like (Hr) region, which contains a diiron metal center, CC cannot bind iron and undergoes conformational changes that destabilize CC the FBXL5 protein and cause its ubiquitination and degradation CC (PubMed:19762596, PubMed:19762597). When intracellular iron levels CC start rising, the Hr region is stabilized (PubMed:19762596, CC PubMed:19762597). Additional increases in iron levels facilitate the CC assembly and incorporation of a redox active [2Fe-2S] cluster in the C- CC terminal domain (PubMed:32126207). Only when oxygen level is high CC enough to maintain the cluster in its oxidized state can FBXL5 recruit CC IRP2 as a substrate for polyubiquitination and degradation CC (PubMed:32126207). Promotes ubiquitination and subsequent degradation CC of the dynactin complex component DCTN1 (PubMed:17532294). Within the CC nucleus, promotes the ubiquitination of SNAI1; preventing its CC interaction with DNA and promoting its degradation (PubMed:24157836). CC Negatively regulates DNA damage response by mediating the ubiquitin- CC proteasome degradation of the DNA repair protein NABP2 CC (PubMed:25249620). {ECO:0000269|PubMed:17532294, CC ECO:0000269|PubMed:19762596, ECO:0000269|PubMed:19762597, CC ECO:0000269|PubMed:32126207}. CC -!- COFACTOR: CC Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135; CC Evidence={ECO:0000269|PubMed:32126207}; CC -!- ACTIVITY REGULATION: An iron-sulfur cluster promotes IRP2 CC polyubiquitination and degradation in response to both iron and oxygen CC concentrations. {ECO:0000269|PubMed:32126207}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. CC Interacts with ACO1/IRP1, IREB2/IRP2; the interaction depends on the CC [2Fe-2S] cluster. Interacts with DCTN1/p150-glued. CC {ECO:0000269|PubMed:17532294, ECO:0000269|PubMed:19762596, CC ECO:0000269|PubMed:19762597}. CC -!- INTERACTION: CC Q9UKA1; O95714: HERC2; NbExp=4; IntAct=EBI-2692340, EBI-1058922; CC Q9UKA1; P48200: IREB2; NbExp=2; IntAct=EBI-2692340, EBI-2805796; CC Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486; CC Q9UKA1; Q13148: TARDBP; NbExp=3; IntAct=EBI-2692340, EBI-372899; CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region CC {ECO:0000269|PubMed:17532294}. Nucleus {ECO:0000269|PubMed:24157836}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9UKA1-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9UKA1-2; Sequence=VSP_008417; CC -!- DOMAIN: The hemerythrin-like region acts as an oxygen and iron sensor CC by binding oxygen through a diiron metal-center. In absence of oxygen CC and iron, the protein is ubiquitinated and degraded. CC {ECO:0000269|PubMed:19762596, ECO:0000269|PubMed:19762597}. CC -!- PTM: Polybiquitinated upon iron and oxygen depletion, leading to its CC degradation by the proteasome. Ubiquitination is regulated by the CC hemerythrin-like region that acts as an oxygen and iron sensor. CC Undergoes constitutive ubiquitin-dependent degradation at the steady CC state by HERC2 (PubMed:24778179). {ECO:0000269|PubMed:19762596, CC ECO:0000269|PubMed:19762597, ECO:0000269|PubMed:24778179}. CC -!- MISCELLANEOUS: Binds a diiron center, that can be bridged by a hydroxo CC group. The hydroxo bridge is not present when FBXL5 is in the reduced CC form and seems to play a critical role in regulating iron binding. CC {ECO:0000269|PubMed:22492618}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF03700.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAF67489.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAD97924.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=EAW92737.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; 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; AF176700; AAF03700.1; ALT_INIT; mRNA. DR EMBL; AF199420; AAF09249.1; -; mRNA. DR EMBL; AF142481; AAF66616.1; -; mRNA. DR EMBL; AK000153; BAA90978.1; -; mRNA. DR EMBL; AK295510; BAG58427.1; -; mRNA. DR EMBL; BX537957; CAD97924.1; ALT_INIT; mRNA. DR EMBL; AC114744; AAY40929.1; -; Genomic_DNA. DR EMBL; AC116651; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471069; EAW92737.1; ALT_SEQ; Genomic_DNA. DR EMBL; CH471069; EAW92739.1; -; Genomic_DNA. DR EMBL; BC030656; AAH30656.1; -; mRNA. DR EMBL; AF157323; AAF67489.1; ALT_INIT; mRNA. DR EMBL; AF174591; AAF04512.1; -; mRNA. DR CCDS; CCDS3415.1; -. [Q9UKA1-1] DR CCDS; CCDS54745.1; -. [Q9UKA1-2] DR RefSeq; NP_001180463.1; NM_001193534.1. DR RefSeq; NP_001180464.1; NM_001193535.2. [Q9UKA1-2] DR RefSeq; NP_036293.1; NM_012161.4. [Q9UKA1-1] DR PDB; 3U9J; X-ray; 1.60 A; A/B=1-160. DR PDB; 3U9M; X-ray; 1.95 A; A/C/E/G=1-160. DR PDB; 3V5X; X-ray; 1.85 A; A/B=1-161. DR PDB; 3V5Y; X-ray; 2.10 A; A/B/C/D=1-161. DR PDB; 3V5Z; X-ray; 2.18 A; A/B=1-161. DR PDB; 6VCD; EM; 3.00 A; B=200-691. DR PDBsum; 3U9J; -. DR PDBsum; 3U9M; -. DR PDBsum; 3V5X; -. DR PDBsum; 3V5Y; -. DR PDBsum; 3V5Z; -. DR PDBsum; 6VCD; -. DR AlphaFoldDB; Q9UKA1; -. DR EMDB; EMD-21149; -. DR SMR; Q9UKA1; -. DR BioGRID; 117625; 47. DR ComplexPortal; CPX-2239; SCF E3 ubiquitin ligase complex, FBXL5 variant. DR FunCoup; Q9UKA1; 558. DR IntAct; Q9UKA1; 34. DR MINT; Q9UKA1; -. DR STRING; 9606.ENSP00000344866; -. DR iPTMnet; Q9UKA1; -. DR PhosphoSitePlus; Q9UKA1; -. DR BioMuta; FBXL5; -. DR DMDM; 37537864; -. DR MassIVE; Q9UKA1; -. DR PaxDb; 9606-ENSP00000344866; -. DR PeptideAtlas; Q9UKA1; -. DR ProteomicsDB; 84748; -. [Q9UKA1-1] DR ProteomicsDB; 84749; -. [Q9UKA1-2] DR Antibodypedia; 9778; 199 antibodies from 29 providers. DR DNASU; 26234; -. DR Ensembl; ENST00000341285.8; ENSP00000344866.3; ENSG00000118564.16. [Q9UKA1-1] DR Ensembl; ENST00000412094.6; ENSP00000408679.2; ENSG00000118564.16. [Q9UKA1-2] DR GeneID; 26234; -. DR KEGG; hsa:26234; -. DR MANE-Select; ENST00000341285.8; ENSP00000344866.3; NM_012161.4; NP_036293.1. DR UCSC; uc003goc.3; human. [Q9UKA1-1] DR AGR; HGNC:13602; -. DR ClinPGx; PA28025; -. DR CTD; 26234; -. DR DisGeNET; 26234; -. DR GeneCards; FBXL5; -. DR HGNC; HGNC:13602; FBXL5. DR HPA; ENSG00000118564; Low tissue specificity. DR MIM; 605655; gene. DR OpenTargets; ENSG00000118564; -. DR VEuPathDB; HostDB:ENSG00000118564; -. DR eggNOG; ENOG502QS5I; Eukaryota. DR GeneTree; ENSGT00390000006172; -. DR HOGENOM; CLU_017503_0_0_1; -. DR InParanoid; Q9UKA1; -. DR OMA; GEMFCGH; -. DR OrthoDB; 10257471at2759; -. DR PAN-GO; Q9UKA1; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q9UKA1; -. DR PathwayCommons; Q9UKA1; -. DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-917937; Iron uptake and transport. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q9UKA1; -. DR SIGNOR; Q9UKA1; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000118564; -. DR BioGRID-ORCS; 26234; 35 hits in 1208 CRISPR screens. DR ChiTaRS; FBXL5; human. DR EvolutionaryTrace; Q9UKA1; -. DR GeneWiki; FBXL5; -. DR GenomeRNAi; 26234; -. DR Pharos; Q9UKA1; Tbio. DR PRO; PR:Q9UKA1; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q9UKA1; protein. DR Bgee; ENSG00000118564; Expressed in monocyte and 215 other cell types or tissues. DR ExpressionAtlas; Q9UKA1; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0000151; C:ubiquitin ligase complex; NAS:UniProtKB. DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; IEA:UniProtKB-KW. DR GO; GO:0005506; F:iron ion binding; IDA:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; NAS:UniProtKB. DR GO; GO:0006879; P:intracellular iron ion homeostasis; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd22118; F-box_FBXL5; 1. DR CDD; cd12109; Hr_FBXL5; 1. DR FunFam; 1.20.1280.50:FF:000007; F-box/LRR-repeat protein 5 isoform X1; 1. DR FunFam; 3.80.10.10:FF:000086; F-box/LRR-repeat protein 5 isoform X1; 1. DR FunFam; 3.80.10.10:FF:000106; F-box/LRR-repeat protein 5 isoform X1; 1. DR FunFam; 1.20.120.520:FF:000002; F-box/LRR-repeat protein 5 isoform X2; 1. DR Gene3D; 1.20.1280.50; -; 1. DR Gene3D; 1.20.120.520; nmb1532 protein domain like; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 2. DR InterPro; IPR036047; F-box-like_dom_sf. DR InterPro; IPR001810; F-box_dom. DR InterPro; IPR012312; Hemerythrin-like. DR InterPro; IPR045808; Hr_FBXL5. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR006553; Leu-rich_rpt_Cys-con_subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR PANTHER; PTHR13318:SF19; F-BOX_LRR-REPEAT PROTEIN 5; 1. DR PANTHER; PTHR13318; PARTNER OF PAIRED, ISOFORM B-RELATED; 1. DR Pfam; PF12937; F-box-like; 1. DR Pfam; PF01814; Hemerythrin; 1. DR Pfam; PF13516; LRR_6; 3. DR SMART; SM00256; FBOX; 1. DR SMART; SM00367; LRR_CC; 4. DR SUPFAM; SSF81383; F-box domain; 1. DR SUPFAM; SSF52047; RNI-like; 1. DR PROSITE; PS50181; FBOX; 1. PE 1: Evidence at protein level; KW 2Fe-2S; 3D-structure; Alternative splicing; Cytoplasm; Iron; Iron-sulfur; KW Leucine-rich repeat; Metal-binding; Nucleus; Proteomics identification; KW Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway. FT CHAIN 1..691 FT /note="F-box/LRR-repeat protein 5" FT /id="PRO_0000119845" FT DOMAIN 202..248 FT /note="F-box" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00080" FT REPEAT 340..364 FT /note="LRR 1" FT REPEAT 365..392 FT /note="LRR 2" FT REPEAT 393..418 FT /note="LRR 3" FT REPEAT 479..508 FT /note="LRR 4" FT REPEAT 576..607 FT /note="LRR 5" FT REPEAT 608..635 FT /note="LRR 6" FT REPEAT 636..661 FT /note="LRR 7" FT REGION 1..159 FT /note="Hemerythrin-like" FT /evidence="ECO:0000269|PubMed:19762596, FT ECO:0000269|PubMed:19762597" FT BINDING 15 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 57 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 58 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 61 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 61 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 80 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 126 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 130 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 130 FT /ligand="Fe(3+)" FT /ligand_id="ChEBI:CHEBI:29034" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:22253436, FT ECO:0000269|PubMed:22492618, ECO:0007744|PDB:3U9J, FT ECO:0007744|PDB:3U9M, ECO:0007744|PDB:3V5X, FT ECO:0007744|PDB:3V5Y, ECO:0007744|PDB:3V5Z" FT BINDING 662 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT /evidence="ECO:0000269|PubMed:32126207, FT ECO:0007744|PDB:6VCD" FT BINDING 676 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT /evidence="ECO:0000269|PubMed:32126207, FT ECO:0007744|PDB:6VCD" FT BINDING 686 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT /evidence="ECO:0000269|PubMed:32126207, FT ECO:0007744|PDB:6VCD" FT BINDING 687 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT /evidence="ECO:0000269|PubMed:32126207, FT ECO:0007744|PDB:6VCD" FT VAR_SEQ 29..45 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:17974005" FT /id="VSP_008417" FT MUTAGEN 15 FT /note="H->A: Abolishes iron-binding and promotes its FT degradation." FT /evidence="ECO:0000269|PubMed:19762596" FT MUTAGEN 57 FT /note="H->A: Abolishes iron-binding and promotes its FT degradation." FT /evidence="ECO:0000269|PubMed:19762596, FT ECO:0000269|PubMed:19762597" FT MUTAGEN 61 FT /note="E->A: Abolishes iron-binding and promotes its FT degradation." FT /evidence="ECO:0000269|PubMed:19762597" FT MUTAGEN 662 FT /note="C->S: More than 90% loss of binding to IREB2/IRP2." FT /evidence="ECO:0000269|PubMed:32126207" FT MUTAGEN 676 FT /note="C->S: More than 90% loss of binding to IREB2/IRP2." FT /evidence="ECO:0000269|PubMed:32126207" FT MUTAGEN 686 FT /note="C->S: More than 90% loss of binding to IREB2/IRP2." FT /evidence="ECO:0000269|PubMed:32126207" FT MUTAGEN 687 FT /note="C->S: More than 90% loss of binding to IREB2/IRP2." FT /evidence="ECO:0000269|PubMed:32126207" FT CONFLICT 52 FT /note="K -> T (in Ref. 8; AAH30656)" FT /evidence="ECO:0000305" FT CONFLICT 195 FT /note="Missing (in Ref. 2; AAF09249)" FT /evidence="ECO:0000305" FT CONFLICT 242 FT /note="G -> R (in Ref. 8; AAH30656)" FT /evidence="ECO:0000305" FT CONFLICT 532 FT /note="V -> I (in Ref. 4; BAA90978)" FT /evidence="ECO:0000305" FT HELIX 6..8 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 12..31 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 37..61 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 62..66 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 67..73 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 85..98 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 102..129 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 130..134 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 135..141 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 144..158 FT /evidence="ECO:0007829|PDB:3U9J" FT HELIX 210..216 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 222..227 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 228..230 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 233..238 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 246..248 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 250..253 FT /evidence="ECO:0007829|PDB:6VCD" FT TURN 254..256 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 312..319 FT /evidence="ECO:0007829|PDB:6VCD" FT TURN 320..323 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 325..328 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 334..336 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 346..349 FT /evidence="ECO:0007829|PDB:6VCD" FT TURN 350..354 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 360..362 FT /evidence="ECO:0007829|PDB:6VCD" FT TURN 370..375 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 378..380 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 387..389 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 400..404 FT /evidence="ECO:0007829|PDB:6VCD" FT TURN 405..408 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 613..617 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 620..623 FT /evidence="ECO:0007829|PDB:6VCD" FT HELIX 641..648 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 663..665 FT /evidence="ECO:0007829|PDB:6VCD" FT TURN 670..672 FT /evidence="ECO:0007829|PDB:6VCD" FT STRAND 682..684 FT /evidence="ECO:0007829|PDB:6VCD" SQ SEQUENCE 691 AA; 78555 MW; 923A1B31590E5145 CRC64; MAPFPEEVDV FTAPHWRMKQ LVGLYCDKLS KTNFSNNNDF RALLQSLYAT FKEFKMHEQI ENEYIIGLLQ QRSQTIYNVH SDNKLSEMLS LFEKGLKNVK NEYEQLNYAK QLKERLEAFT RDFLPHMKEE EEVFQPMLME YFTYEELKDI KKKVIAQHCS QKDTAELLRG LSLWNHAEER QKFFKYSVDE KSDKEAEVSE HSTGITHLPP EVMLSIFSYL NPQELCRCSQ VSMKWSQLTK TGSLWKHLYP VHWARGDWYS GPATELDTEP DDEWVKNRKD ESRAFHEWDE DADIDESEES AEESIAISIA QMEKRLLHGL IHNVLPYVGT SVKTLVLAYS SAVSSKMVRQ ILELCPNLEH LDLTQTDISD SAFDSWSWLG CCQSLRHLDL SGCEKITDVA LEKISRALGI LTSHQSGFLK TSTSKITSTA WKNKDITMQS TKQYACLHDL TNKGIGEEID NEHPWTKPVS SENFTSPYVW MLDAEDLADI EDTVEWRHRN VESLCVMETA SNFSCSTSGC FSKDIVGLRT SVCWQQHCAS PAFAYCGHSF CCTGTALRTM SSLPESSAMC RKAARTRLPR GKDLIYFGSE KSDQETGRVL LFLSLSGCYQ ITDHGLRVLT LGGGLPYLEH LNLSGCLTIT GAGLQDLVSA CPSLNDEYFY YCDNINGPHA DTASGCQNLQ CGFRACCRSG E //