FBXL3_HUMAN
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 03-AUG-2022, entry version 167.
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.
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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 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; Q9UKT7; -.
DR PeptideAtlas; Q9UKT7; -.
DR PRIDE; Q9UKT7; -.
DR ProteomicsDB; 84852; -.
DR Antibodypedia; 24515; 215 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 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; ENSQTCD; -.
DR OrthoDB; 1027299at2759; -.
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 UniPathway; UPA00143; -.
DR BioGRID-ORCS; 26224; 15 hits in 1120 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 191 other tissues.
DR ExpressionAtlas; Q9UKT7; baseline and differential.
DR Genevisible; Q9UKT7; HS.
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:0000086; P:G2/M transition of mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0031648; P:protein destabilization; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central.
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 Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR036047; F-box-like_dom_sf.
DR InterPro; IPR001810; F-box_dom.
DR InterPro; IPR032675; LRR_dom_sf.
DR Pfam; PF12937; F-box-like; 1.
DR SMART; SM00256; FBOX; 1.
DR SUPFAM; SSF81383; SSF81383; 1.
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
