ID FBXL4_HUMAN Reviewed; 621 AA. AC Q9UKA2; B2R7Q5; E1P530; O95919; Q5BJH0; Q9UJU0; DT 27-MAY-2002, integrated into UniProtKB/Swiss-Prot. DT 27-MAY-2002, sequence version 2. DT 27-MAR-2024, entry version 187. DE RecName: Full=F-box/LRR-repeat protein 4; DE AltName: Full=F-box and leucine-rich repeat protein 4; DE AltName: Full=F-box protein FBL4/FBL5; GN Name=FBXL4; Synonyms=FBL4, FBL5; 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], TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. 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]. 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 [3] RP NUCLEOTIDE SEQUENCE [MRNA]. 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=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 GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [6] 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye, and PNS; 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 [8] RP SUBCELLULAR LOCATION, AND INVOLVEMENT IN MTDPS13. RX PubMed=23993193; DOI=10.1016/j.ajhg.2013.07.017; RA Bonnen P.E., Yarham J.W., Besse A., Wu P., Faqeih E.A., Al-Asmari A.M., RA Saleh M.A., Eyaid W., Hadeel A., He L., Smith F., Yau S., Simcox E.M., RA Miwa S., Donti T., Abu-Amero K.K., Wong L.J., Craigen W.J., Graham B.H., RA Scott K.L., McFarland R., Taylor R.W.; RT "Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of RT mitochondrial DNA maintenance."; RL Am. J. Hum. Genet. 93:471-481(2013). RN [9] RP SUBCELLULAR LOCATION, AND VARIANTS MTDPS13 THR-205; TRP-482; ASN-551; RP GLY-565; ALA-568 AND PRO-597. RX PubMed=23993194; DOI=10.1016/j.ajhg.2013.07.016; RA Gai X., Ghezzi D., Johnson M.A., Biagosch C.A., Shamseldin H.E., RA Haack T.B., Reyes A., Tsukikawa M., Sheldon C.A., Srinivasan S., Gorza M., RA Kremer L.S., Wieland T., Strom T.M., Polyak E., Place E., Consugar M., RA Ostrovsky J., Vidoni S., Robinson A.J., Wong L.J., Sondheimer N., RA Salih M.A., Al-Jishi E., Raab C.P., Bean C., Furlan F., Parini R., RA Lamperti C., Mayr J.A., Konstantopoulou V., Huemer M., Pierce E.A., RA Meitinger T., Freisinger P., Sperl W., Prokisch H., Alkuraya F.S., RA Falk M.J., Zeviani M.; RT "Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset RT mitochondrial encephalomyopathy."; RL Am. J. Hum. Genet. 93:482-495(2013). RN [10] RP VARIANT MTDPS13 PRO-481. RX PubMed=27182039; DOI=10.1016/j.ejmg.2016.05.005; RA Baroey T., Pedurupillay C.R., Bliksrud Y.T., Rasmussen M., Holmgren A., RA Vigeland M.D., Hughes T., Brink M., Rodenburg R., Nedregaard B., RA Stroemme P., Frengen E., Misceo D.; RT "A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic RT mitochondrial DNA depletion syndrome 13."; RL Eur. J. Med. Genet. 59:342-346(2016). CC -!- SUBUNIT: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. CC {ECO:0000250}. CC -!- INTERACTION: CC Q9UKA2; P50570-2: DNM2; NbExp=3; IntAct=EBI-2869903, EBI-10968534; CC Q9UKA2; O14773: TPP1; NbExp=3; IntAct=EBI-2869903, EBI-2800203; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Mitochondrion. CC -!- TISSUE SPECIFICITY: Expressed in heart, kidney, liver, lung, pancreas, CC and placenta, but not in skeletal muscle. CC {ECO:0000269|PubMed:10531037}. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 13 (MTDPS13) CC [MIM:615471]: An autosomal recessive disorder characterized by early CC infantile onset of encephalopathy, hypotonia, lactic acidosis, and CC severe global developmental delay. Cells derived from patient tissues CC show defects in mitochondrial oxidative phosphorylation and decreased CC mtDNA content. {ECO:0000269|PubMed:23993193, CC ECO:0000269|PubMed:23993194, ECO:0000269|PubMed:27182039}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. 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; AF176699; AAF03699.1; -; mRNA. DR EMBL; AF174590; AAF04511.1; -; mRNA. DR EMBL; AF199355; AAF09247.1; -; mRNA. DR EMBL; AK313076; BAG35902.1; -; mRNA. DR EMBL; AL022395; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW48489.1; -; Genomic_DNA. DR EMBL; CH471051; EAW48490.1; -; Genomic_DNA. DR EMBL; BC055010; AAH55010.1; -; mRNA. DR EMBL; BC091484; AAH91484.1; -; mRNA. DR CCDS; CCDS5041.1; -. DR RefSeq; NP_001265645.1; NM_001278716.1. DR RefSeq; NP_036292.2; NM_012160.4. DR RefSeq; XP_016866215.1; XM_017010726.1. DR AlphaFoldDB; Q9UKA2; -. DR SMR; Q9UKA2; -. DR BioGRID; 117626; 65. DR ComplexPortal; CPX-2512; SCF E3 ubiquitin ligase complex, FBXL4 variant. DR IntAct; Q9UKA2; 40. DR STRING; 9606.ENSP00000358247; -. DR GlyGen; Q9UKA2; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9UKA2; -. DR PhosphoSitePlus; Q9UKA2; -. DR SwissPalm; Q9UKA2; -. DR BioMuta; FBXL4; -. DR DMDM; 21263631; -. DR EPD; Q9UKA2; -. DR jPOST; Q9UKA2; -. DR MassIVE; Q9UKA2; -. DR MaxQB; Q9UKA2; -. DR PaxDb; 9606-ENSP00000358247; -. DR PeptideAtlas; Q9UKA2; -. DR ProteomicsDB; 84750; -. DR Pumba; Q9UKA2; -. DR Antibodypedia; 18894; 125 antibodies from 20 providers. DR DNASU; 26235; -. DR Ensembl; ENST00000229971.2; ENSP00000229971.1; ENSG00000112234.9. DR Ensembl; ENST00000369244.7; ENSP00000358247.1; ENSG00000112234.9. DR GeneID; 26235; -. DR KEGG; hsa:26235; -. DR MANE-Select; ENST00000369244.7; ENSP00000358247.1; NM_001278716.2; NP_001265645.1. DR UCSC; uc003ppf.2; human. DR AGR; HGNC:13601; -. DR CTD; 26235; -. DR DisGeNET; 26235; -. DR GeneCards; FBXL4; -. DR GeneReviews; FBXL4; -. DR HGNC; HGNC:13601; FBXL4. DR HPA; ENSG00000112234; Low tissue specificity. DR MalaCards; FBXL4; -. DR MIM; 605654; gene. DR MIM; 615471; phenotype. DR neXtProt; NX_Q9UKA2; -. DR OpenTargets; ENSG00000112234; -. DR Orphanet; 369897; Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies. DR PharmGKB; PA28024; -. DR VEuPathDB; HostDB:ENSG00000112234; -. DR eggNOG; KOG1947; Eukaryota. DR GeneTree; ENSGT00940000155184; -. DR HOGENOM; CLU_024764_2_0_1; -. DR InParanoid; Q9UKA2; -. DR OMA; GWCMREA; -. DR OrthoDB; 540011at2759; -. DR PhylomeDB; Q9UKA2; -. DR TreeFam; TF323721; -. DR PathwayCommons; Q9UKA2; -. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q9UKA2; -. DR BioGRID-ORCS; 26235; 6 hits in 1196 CRISPR screens. DR ChiTaRS; FBXL4; human. DR GenomeRNAi; 26235; -. DR Pharos; Q9UKA2; Tbio. DR PRO; PR:Q9UKA2; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q9UKA2; Protein. DR Bgee; ENSG00000112234; Expressed in adrenal tissue and 181 other cell types or tissues. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005758; C:mitochondrial intermembrane space; IDA:UniProtKB. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IBA:GO_Central. DR GO; GO:0000151; C:ubiquitin ligase complex; TAS:ProtInc. DR GO; GO:0000422; P:autophagy of mitochondrion; IMP:MGI. DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IBA:GO_Central. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; TAS:ProtInc. DR CDD; cd22117; F-box_FBXL4; 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; IPR006553; Leu-rich_rpt_Cys-con_subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR PANTHER; PTHR13318:SF152; F-BOX_LRR-REPEAT PROTEIN 4; 1. DR PANTHER; PTHR13318; UNCHARACTERIZED; 1. DR Pfam; PF12937; F-box-like; 1. DR SMART; SM00367; LRR_CC; 7. DR SUPFAM; SSF81383; F-box domain; 1. DR SUPFAM; SSF52047; RNI-like; 1. DR PROSITE; PS50181; FBOX; 1. DR Genevisible; Q9UKA2; HS. PE 1: Evidence at protein level; KW Cytoplasm; Disease variant; Leucine-rich repeat; Methylation; KW Mitochondrion; Nucleus; Primary mitochondrial disease; Reference proteome; KW Repeat; Ubl conjugation pathway. FT CHAIN 1..621 FT /note="F-box/LRR-repeat protein 4" FT /id="PRO_0000119844" FT DOMAIN 277..332 FT /note="F-box" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00080" FT REPEAT 376..397 FT /note="LRR 1" FT REPEAT 402..421 FT /note="LRR 2" FT REPEAT 427..448 FT /note="LRR 3" FT REPEAT 452..474 FT /note="LRR 4" FT REPEAT 480..501 FT /note="LRR 5" FT REPEAT 504..524 FT /note="LRR 6" FT REPEAT 532..558 FT /note="LRR 7" FT REPEAT 559..583 FT /note="LRR 8" FT REPEAT 584..609 FT /note="LRR 9" FT MOD_RES 28 FT /note="Asymmetric dimethylarginine" FT /evidence="ECO:0000250|UniProtKB:Q8BH70" FT VARIANT 205 FT /note="I -> T (in MTDPS13; dbSNP:rs1350566881)" FT /evidence="ECO:0000269|PubMed:23993194" FT /id="VAR_070858" FT VARIANT 481 FT /note="L -> P (in MTDPS13; dbSNP:rs772037717)" FT /evidence="ECO:0000269|PubMed:27182039" FT /id="VAR_076547" FT VARIANT 482 FT /note="R -> W (in MTDPS13; dbSNP:rs398123061)" FT /evidence="ECO:0000269|PubMed:23993194" FT /id="VAR_070859" FT VARIANT 551 FT /note="I -> N (in MTDPS13; dbSNP:rs1554215979)" FT /evidence="ECO:0000269|PubMed:23993194" FT /id="VAR_070860" FT VARIANT 565 FT /note="D -> G (in MTDPS13; dbSNP:rs398123062)" FT /evidence="ECO:0000269|PubMed:23993194" FT /id="VAR_070861" FT VARIANT 568 FT /note="G -> A (in MTDPS13; dbSNP:rs398123060)" FT /evidence="ECO:0000269|PubMed:23993194" FT /id="VAR_070862" FT VARIANT 597 FT /note="Q -> P (in MTDPS13; dbSNP:rs201989042)" FT /evidence="ECO:0000269|PubMed:23993194" FT /id="VAR_070863" FT CONFLICT 5 FT /note="F -> Y (in Ref. 1; AAF03699)" FT /evidence="ECO:0000305" FT CONFLICT 42 FT /note="S -> G (in Ref. 3; AAF09247)" FT /evidence="ECO:0000305" FT CONFLICT 122 FT /note="Q -> K (in Ref. 1; AAF03699)" FT /evidence="ECO:0000305" FT CONFLICT 126 FT /note="Y -> I (in Ref. 1; AAF03699)" FT /evidence="ECO:0000305" FT CONFLICT 219 FT /note="E -> G (in Ref. 1; AAF03699)" FT /evidence="ECO:0000305" FT CONFLICT 232 FT /note="P -> A (in Ref. 1; AAF03699)" FT /evidence="ECO:0000305" FT CONFLICT 533 FT /note="P -> L (in Ref. 4; BAG35902)" FT /evidence="ECO:0000305" SQ SEQUENCE 621 AA; 70097 MW; D8FD51A5C4F922D3 CRC64; MSPVFPMLTV LTMFYYICLR RRARTATRGE MMNTHRAIES NSQTSPLNAE VVQYAKEVVD FSSHYGSENS MSYTMWNLAG VPNVFPSSGD FTQTAVFRTY GTWWDQCPSA SLPFKRTPPN FQSQDYVELT FEQQVYPTAV HVLETYHPGA VIRILACSAN PYSPNPPAEV RWEILWSERP TKVNASQARQ FKPCIKQINF PTNLIRLEVN SSLLEYYTEL DAVVLHGVKD KPVLSLKTSL IDMNDIEDDA YAEKDGCGMD SLNKKFSSAV LGEGPNNGYF DKLPYELIQL ILNHLTLPDL CRLAQTCKLL SQHCCDPLQY IHLNLQPYWA KLDDTSLEFL QSRCTLVQWL NLSWTGNRGF ISVAGFSRFL KVCGSELVRL ELSCSHFLNE TCLEVISEMC PNLQALNLSS CDKLPPQAFN HIAKLCSLKR LVLYRTKVEQ TALLSILNFC SELQHLSLGS CVMIEDYDVI ASMIGAKCKK LRTLDLWRCK NITENGIAEL ASGCPLLEEL DLGWCPTLQS STGCFTRLAH QLPNLQKLFL TANRSVCDTD IDELACNCTR LQQLDILGTR MVSPASLRKL LESCKDLSLL DVSFCSQIDN RAVLELNASF PKVFIKKSFT Q //