ID FBXL3_HUMAN Reviewed; 428 AA. AC Q9UKT7; B2RB04; Q9P122; DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 27-MAR-2024, entry version 176. DE RecName: Full=F-box/LRR-repeat protein 3; DE AltName: Full=F-box and leucine-rich repeat protein 3A; DE AltName: Full=F-box/LRR-repeat protein 3A; GN Name=FBXL3; Synonyms=FBL3A, FBXL3A; 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=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 [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Klockars T., Holmberg V., Savukoski M., Lander E.S., Peltonen L.; RT "Transcript mapping on the CLN5 region on 13q22."; RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; 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 MRNA]. RC TISSUE=Skin; 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 FUNCTION IN CIRCADIAN CLOCK, INTERACTION WITH CRY1 AND CRY2, AND RP MUTAGENESIS OF CYS-358. RX PubMed=17463251; DOI=10.1126/science.1141194; RA Busino L., Bassermann F., Maiolica A., Lee C., Nolan P.M., Godinho S.I., RA Draetta G.F., Pagano M.; RT "SCFFbxl3 controls the oscillation of the circadian clock by directing the RT degradation of cryptochrome proteins."; RL Science 316:900-904(2007). RN [6] RP FUNCTION IN CIRCADIAN CLOCK. RX PubMed=23452855; DOI=10.1016/j.cell.2013.01.055; RA Yoo S.H., Mohawk J.A., Siepka S.M., Shan Y., Huh S.K., Hong H.K., RA Kornblum I., Kumar V., Koike N., Xu M., Nussbaum J., Liu X., Chen Z., RA Chen Z.J., Green C.B., Takahashi J.S.; RT "Competing E3 ubiquitin ligases govern circadian periodicity by degradation RT of CRY in nucleus and cytoplasm."; RL Cell 152:1091-1105(2013). RN [7] RP FUNCTION. RX PubMed=27565346; DOI=10.1016/j.cell.2016.07.027; RA Scott D.C., Rhee D.Y., Duda D.M., Kelsall I.R., Olszewski J.L., Paulo J.A., RA de Jong A., Ovaa H., Alpi A.F., Harper J.W., Schulman B.A.; RT "Two distinct types of E3 ligases work in unison to regulate substrate RT ubiquitylation."; RL Cell 166:1198-1214(2016). RN [8] RP INVOLVEMENT IN IDDSFAS, AND VARIANTS IDDSFAS 149-ARG--TRP-428 DEL AND RP ARG-358. RX PubMed=30481285; DOI=10.1093/hmg/ddy406; RA Ansar M., Paracha S.A., Serretti A., Sarwar M.T., Khan J., Ranza E., RA Falconnet E., Iwaszkiewicz J., Shah S.F., Qaisar A.A., Santoni F.A., RA Zoete V., Megarbane A., Ahmed J., Colombo R., Makrythanasis P., RA Antonarakis S.E.; RT "Biallelic variants in FBXL3 cause intellectual disability, delayed motor RT development and short stature."; RL Hum. Mol. Genet. 28:972-979(2019). CC -!- FUNCTION: Substrate-recognition component of the SCF(FBXL3) E3 CC ubiquitin ligase complex involved in circadian rhythm function. Plays a CC key role in the maintenance of both the speed and the robustness of the CC circadian clock oscillation (PubMed:17463251, PubMed:23452855, CC PubMed:27565346). The SCF(FBXL3) complex mainly acts in the nucleus and CC mediates ubiquitination and subsequent degradation of CRY1 and CRY2 CC (PubMed:17463251, PubMed:23452855, PubMed:27565346). Activity of the CC SCF(FBXL3) complex is counteracted by the SCF(FBXL21) complex CC (PubMed:23452855). {ECO:0000269|PubMed:17463251, CC ECO:0000269|PubMed:23452855, ECO:0000269|PubMed:27565346}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase CC complex SCF(FBXL3) composed of CUL1, SKP1, RBX1 and FBXL3 (By CC similarity). Interacts with CRY1 and CRY2 (phosphorylated) CC (PubMed:17463251). Interacts with HDAC3 (By similarity). Interacts with CC KDM8 (By similarity). {ECO:0000250|UniProtKB:Q8C4V4, CC ECO:0000269|PubMed:17463251}. CC -!- INTERACTION: CC Q9UKT7; Q86XR8-3: CEP57; NbExp=3; IntAct=EBI-2557269, EBI-11752486; CC Q9UKT7; Q9UJ68: MSRA; NbExp=3; IntAct=EBI-2557269, EBI-19157918; CC Q9UKT7; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-2557269, EBI-79165; CC Q9UKT7; Q9R194: Cry2; Xeno; NbExp=13; IntAct=EBI-2557269, EBI-1266619; CC Q9UKT7; Q9WTX5: Skp1; Xeno; NbExp=4; IntAct=EBI-2557269, EBI-1202363; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:10531035}. Cytoplasm CC {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:10531035}. CC -!- PTM: Undergoes autophagy-mediated degradation in the liver in a time- CC dependent manner. {ECO:0000250|UniProtKB:Q8C4V4}. CC -!- DISEASE: Intellectual developmental disorder with short stature, facial CC anomalies, and speech defects (IDDSFAS) [MIM:606220]: An autosomal CC recessive disorder characterized by global developmental delay, mildly CC to severely impaired intellectual development, delayed or slurred CC speech, and short stature. Dysmorphic features included a large bulbous CC nose and variable microretrognathia. Some patients show joint CC hyperlaxity and dislocations. {ECO:0000269|PubMed:30481285}. 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; AF129532; AAF04466.1; -; mRNA. DR EMBL; AF126028; AAF37383.1; -; mRNA. DR EMBL; AK314442; BAG37051.1; -; mRNA. DR EMBL; BC072448; AAH72448.1; -; mRNA. DR CCDS; CCDS9457.1; -. DR RefSeq; NP_036290.1; NM_012158.2. DR RefSeq; XP_005266393.1; XM_005266336.1. DR PDB; 4I6J; X-ray; 2.70 A; B=1-428. DR PDBsum; 4I6J; -. DR AlphaFoldDB; Q9UKT7; -. DR SMR; Q9UKT7; -. DR BioGRID; 117615; 23. DR ComplexPortal; CPX-3291; SCF E3 ubiquitin ligase complex, FBXL3 variant. DR CORUM; Q9UKT7; -. DR DIP; DIP-40770N; -. DR IntAct; Q9UKT7; 14. DR MINT; Q9UKT7; -. DR STRING; 9606.ENSP00000347834; -. DR iPTMnet; Q9UKT7; -. DR PhosphoSitePlus; Q9UKT7; -. DR BioMuta; FBXL3; -. DR DMDM; 37537866; -. DR EPD; Q9UKT7; -. DR jPOST; Q9UKT7; -. DR MassIVE; Q9UKT7; -. DR MaxQB; Q9UKT7; -. DR PaxDb; 9606-ENSP00000347834; -. DR PeptideAtlas; Q9UKT7; -. DR ProteomicsDB; 84852; -. DR Pumba; Q9UKT7; -. DR Antibodypedia; 24515; 227 antibodies from 32 providers. DR DNASU; 26224; -. DR Ensembl; ENST00000355619.10; ENSP00000347834.5; ENSG00000005812.11. DR GeneID; 26224; -. DR KEGG; hsa:26224; -. DR MANE-Select; ENST00000355619.10; ENSP00000347834.5; NM_012158.4; NP_036290.1. DR UCSC; uc001vkd.4; human. DR AGR; HGNC:13599; -. DR CTD; 26224; -. DR DisGeNET; 26224; -. DR GeneCards; FBXL3; -. DR HGNC; HGNC:13599; FBXL3. DR HPA; ENSG00000005812; Low tissue specificity. DR MalaCards; FBXL3; -. DR MIM; 605653; gene. DR MIM; 606220; phenotype. DR neXtProt; NX_Q9UKT7; -. DR OpenTargets; ENSG00000005812; -. DR PharmGKB; PA28022; -. DR VEuPathDB; HostDB:ENSG00000005812; -. DR eggNOG; KOG1947; Eukaryota. DR GeneTree; ENSGT00940000159395; -. DR HOGENOM; CLU_033637_0_0_1; -. DR InParanoid; Q9UKT7; -. DR OMA; HFHTIEK; -. DR OrthoDB; 2876716at2759; -. DR PhylomeDB; Q9UKT7; -. DR TreeFam; TF352583; -. DR PathwayCommons; Q9UKT7; -. DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis. DR Reactome; R-HSA-400253; Circadian Clock. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q9UKT7; -. DR SIGNOR; Q9UKT7; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 26224; 15 hits in 1197 CRISPR screens. DR ChiTaRS; FBXL3; human. DR GeneWiki; FBXL3; -. DR GenomeRNAi; 26224; -. DR Pharos; Q9UKT7; Tbio. DR PRO; PR:Q9UKT7; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; Q9UKT7; Protein. DR Bgee; ENSG00000005812; Expressed in cardiac muscle of right atrium and 193 other cell types or tissues. DR ExpressionAtlas; Q9UKT7; baseline and differential. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0005634; C:nucleus; ISS: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:0004842; F:ubiquitin-protein transferase activity; NAS:UniProtKB. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB. DR GO; GO:0031648; P:protein destabilization; ISS:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW. DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR CDD; cd22178; F-box_FBXL3; 1. DR Gene3D; 1.20.1280.50; -; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1. DR InterPro; IPR036047; F-box-like_dom_sf. DR InterPro; IPR001810; F-box_dom. DR InterPro; IPR032675; LRR_dom_sf. DR PANTHER; PTHR10224; ES1 PROTEIN HOMOLOG, MITOCHONDRIAL; 1. DR PANTHER; PTHR10224:SF18; F-BOX DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF12937; F-box-like; 1. DR SMART; SM00256; FBOX; 1. DR SUPFAM; SSF81383; F-box domain; 1. DR SUPFAM; SSF52047; RNI-like; 1. DR Genevisible; Q9UKT7; HS. PE 1: Evidence at protein level; KW 3D-structure; Biological rhythms; Cytoplasm; Disease variant; Dwarfism; KW Intellectual disability; Leucine-rich repeat; Nucleus; Reference proteome; KW Repeat; Ubl conjugation pathway. FT CHAIN 1..428 FT /note="F-box/LRR-repeat protein 3" FT /id="PRO_0000119842" FT DOMAIN 34..81 FT /note="F-box" FT REPEAT 119..146 FT /note="LRR 1" FT REPEAT 181..207 FT /note="LRR 2" FT REPEAT 208..233 FT /note="LRR 3" FT REPEAT 234..259 FT /note="LRR 4" FT REPEAT 316..341 FT /note="LRR 5" FT REPEAT 343..368 FT /note="LRR 6" FT REPEAT 369..394 FT /note="LRR 7" FT REGION 1..27 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 149..428 FT /note="Missing (in IDDSFAS)" FT /evidence="ECO:0000269|PubMed:30481285" FT /id="VAR_082209" FT VARIANT 358 FT /note="C -> R (in IDDSFAS; dbSNP:rs1566225872)" FT /evidence="ECO:0000269|PubMed:30481285" FT /id="VAR_082210" FT MUTAGEN 358 FT /note="C->A: Loss of binding with CRY1." FT /evidence="ECO:0000269|PubMed:17463251" FT MUTAGEN 358 FT /note="C->S: Decrease in binding efficiency with CRY2 and FT of CRY2 ubiquitination efficiency, loss of binding with FT CRY1." FT /evidence="ECO:0000269|PubMed:17463251" FT CONFLICT 10 FT /note="R -> H (in Ref. 2; AAF37383)" FT /evidence="ECO:0000305" FT CONFLICT 13 FT /note="S -> A (in Ref. 2; AAF37383)" FT /evidence="ECO:0000305" FT CONFLICT 353 FT /note="R -> A (in Ref. 2; AAF37383)" FT /evidence="ECO:0000305" FT CONFLICT 364 FT /note="I -> V (in Ref. 3; BAG37051)" FT /evidence="ECO:0000305" FT CONFLICT 412 FT /note="V -> A (in Ref. 3; BAG37051)" FT /evidence="ECO:0000305" FT HELIX 42..48 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 53..59 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 64..67 FT /evidence="ECO:0007829|PDB:4I6J" FT TURN 68..71 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 73..76 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 77..83 FT /evidence="ECO:0007829|PDB:4I6J" FT TURN 86..88 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 89..91 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 96..106 FT /evidence="ECO:0007829|PDB:4I6J" FT TURN 107..109 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 112..117 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 121..131 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 140..149 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 151..154 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 157..170 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 176..178 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 186..196 FT /evidence="ECO:0007829|PDB:4I6J" FT TURN 197..199 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 202..204 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 213..222 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 228..232 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 233..235 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 238..245 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 246..249 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 253..260 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 274..283 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 288..294 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 303..306 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 312..317 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 321..328 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 335..340 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 348..357 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 363..366 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 373..382 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 384..386 FT /evidence="ECO:0007829|PDB:4I6J" FT STRAND 388..393 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 394..396 FT /evidence="ECO:0007829|PDB:4I6J" FT HELIX 405..416 FT /evidence="ECO:0007829|PDB:4I6J" SQ SEQUENCE 428 AA; 48707 MW; AAEAB31BAF0EA5A5 CRC64; MKRGGRDSDR NSSEEGTAEK SKKLRTTNEH SQTCDWGNLL QDIILQVFKY LPLLDRAHAS QVCRNWNQVF HMPDLWRCFE FELNQPATSY LKATHPELIK QIIKRHSNHL QYVSFKVDSS KESAEAACDI LSQLVNCSLK TLGLISTARP SFMDLPKSHF ISALTVVFVN SKSLSSLKID DTPVDDPSLK VLVANNSDTL KLLKMSSCPH VSPAGILCVA DQCHGLRELA LNYHLLSDEL LLALSSEKHV RLEHLRIDVV SENPGQTHFH TIQKSSWDAF IRHSPKVNLV MYFFLYEEEF DPFFRYEIPA THLYFGRSVS KDVLGRVGMT CPRLVELVVC ANGLRPLDEE LIRIAERCKN LSAIGLGECE VSCSAFVEFV KMCGGRLSQL SIMEEVLIPD QKYSLEQIHW EVSKHLGRVW FPDMMPTW //