ID   FBX43_HUMAN             Reviewed;         708 AA.
AC   Q4G163;
DT   25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT   10-JUL-2007, sequence version 3.
DT   10-JUN-2026, entry version 146.
DE   RecName: Full=F-box only protein 43;
DE   AltName: Full=Endogenous meiotic inhibitor 2;
GN   Name=FBXO43; Synonyms=EMI2;
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 GENOMIC DNA].
RX   PubMed=16421571; DOI=10.1038/nature04406;
RA   Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA   Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA   Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA   Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA   Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA   Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA   Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA   Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA   Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA   O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA   Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA   Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA   Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA   Platzer M., Shimizu N., Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 8.";
RL   Nature 439:331-335(2006).
RN   [2]
RP   NOMENCLATURE.
RX   PubMed=15520277; DOI=10.1101/gad.1255304;
RA   Jin J., Cardozo T., Lovering R.C., Elledge S.J., Pagano M., Harper J.W.;
RT   "Systematic analysis and nomenclature of mammalian F-box proteins.";
RL   Genes Dev. 18:2573-2580(2004).
RN   [3]
RP   UBIQUITINATION, PHOSPHORYLATION AT SER-76 AND SER-334, AND MUTAGENESIS OF
RP   75-ASP-SER-76 AND 333-ASP-SER-334.
RX   PubMed=15753281; DOI=10.1073/pnas.0501108102;
RA   Tung J.J., Hansen D.V., Ban K.H., Loktev A.V., Summers M.K.,
RA   Adler J.R. III, Jackson P.K.;
RT   "A role for the anaphase-promoting complex inhibitor Emi2/XErp1, a homolog
RT   of early mitotic inhibitor 1, in cytostatic factor arrest of Xenopus
RT   eggs.";
RL   Proc. Natl. Acad. Sci. U.S.A. 102:4318-4323(2005).
RN   [4]
RP   PHOSPHORYLATION AT THR-234.
RX   PubMed=16407128; DOI=10.1073/pnas.0509549102;
RA   Hansen D.V., Tung J.J., Jackson P.K.;
RT   "CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic
RT   factor Emi2/XErp1 to trigger its destruction and meiotic exit.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:608-613(2006).
RN   [5]
RP   INVOLVEMENT IN SPGF64, VARIANT SPGF64 ASP-664, AND VARIANTS GLY-98;
RP   ALA-149; LEU-250 AND GLY-594.
RX   PubMed=30878252; DOI=10.1016/j.fertnstert.2019.01.007;
RA   Ma Y., Xie N., Xie D., Sun L., Li S., Li P., Li Y., Li J., Dong Z., Xie X.;
RT   "A novel homozygous FBXO43 mutation associated with male infertility and
RT   teratozoospermia in a consanguineous Chinese family.";
RL   Fertil. Steril. 111:909.e1-917.e1(2019).
RN   [6]
RP   INVOLVEMENT IN OZEMA12, VARIANT OZEMA12 583-GLN--LEU-708 DEL,
RP   CHARACTERIZATION OF VARIANT OZEMA12 583-GLN--LEU-708 DEL, AND FUNCTION.
RX   PubMed=34052850; DOI=10.1093/humrep/deab131;
RA   Wang W., Wang W., Xu Y., Shi J., Fu J., Chen B., Mu J., Zhang Z., Zhao L.,
RA   Lin J., Du J., Li Q., He L., Jin L., Sun X., Wang L., Sang Q.;
RT   "FBXO43 variants in patients with female infertility characterized by early
RT   embryonic arrest.";
RL   Hum. Reprod. 36:2392-2402(2021).
RN   [7]
RP   VARIANT SPGF64 583-GLN--LEU-708 DEL, TISSUE SPECIFICITY, SUBUNIT, AND
RP   FUNCTION.
RX   PubMed=34595750; DOI=10.1111/cge.14069;
RA   Wu H., Zhang X., Shen Q., Liu Y., Gao Y., Wang G., Lv M., Hua R., Xu Y.,
RA   Zhou P., Wei Z., Tao F., He X., Cao Y., Liu M.;
RT   "A homozygous loss-of-function mutation in FBXO43 causes human non-
RT   obstructive azoospermia.";
RL   Clin. Genet. 101:55-64(2022).
CC   -!- FUNCTION: Required to establish and maintain the arrest of oocytes at
CC       the second meiotic metaphase until fertilization. Acts by inhibiting
CC       the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase.
CC       Probably recognizes and binds to some phosphorylated proteins and
CC       promotes their ubiquitination and degradation (PubMed:34052850,
CC       PubMed:34595750). Plays a vital role in modulating the ubiquitilation
CC       of CCNB1 and CDK1 during gametogenesis. {ECO:0000250|UniProtKB:Q8CDI2,
CC       ECO:0000269|PubMed:34052850, ECO:0000269|PubMed:34595750}.
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBUNIT: Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
CC       According to PubMed:34595750 interaction with SKP1 does not occur.
CC       Interacts with ANAPC2; the interaction is direct, ANAPC4, CDC16, CDC23;
CC       the interaction is direct, ANAPC10; the interaction is direct and
CC       CDC26, during spermatogenesis (PubMed:34595750). May interact with
CC       CDC20 (By similarity). {ECO:0000250|UniProtKB:Q8CDI2,
CC       ECO:0000269|PubMed:34595750}.
CC   -!- INTERACTION:
CC       Q4G163; P30153: PPP2R1A; NbExp=3; IntAct=EBI-12053217, EBI-302388;
CC       Q4G163; P63208: SKP1; NbExp=3; IntAct=EBI-12053217, EBI-307486;
CC   -!- TISSUE SPECIFICITY: Expressed in the testis.
CC       {ECO:0000269|PubMed:34595750}.
CC   -!- PTM: Phosphorylated on Ser-76, Thr-234 and Ser-334 in response to
CC       calcium, which is a prerequisite for ubiquitination and proteasomal
CC       degradation. {ECO:0000305|PubMed:15753281,
CC       ECO:0000305|PubMed:16407128}.
CC   -!- PTM: Ubiquitinated in response to calcium, which promotes proteasomal
CC       degradation. {ECO:0000269|PubMed:15753281}.
CC   -!- DISEASE: Oocyte/zygote/embryo maturation arrest 12 (OZEMA12)
CC       [MIM:619697]: An autosomal recessive disorder characterized by
CC       infertility due to early embryonic arrest.
CC       {ECO:0000269|PubMed:34052850}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Spermatogenic failure 64 (SPGF64) [MIM:619696]: An autosomal
CC       recessive male infertility disorder characterized by
CC       oligoasthenoteratozoospermia or non-obstructive azoospermia. Some
CC       patients have absent sperm due to meiotic arrest at the diplotene
CC       stage. Others show low sperm counts and reduced progressive motility.
CC       {ECO:0000269|PubMed:30878252, ECO:0000269|PubMed:34595750}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
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DR   EMBL; AC021590; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS47904.1; -.
DR   RefSeq; NP_001025031.2; NM_001029860.4.
DR   AlphaFoldDB; Q4G163; -.
DR   SMR; Q4G163; -.
DR   BioGRID; 130316; 74.
DR   ComplexPortal; CPX-8002; SCF E3 ubiquitin ligase complex, FBXO43 variant.
DR   ELM; Q4G163; -.
DR   FunCoup; Q4G163; 1324.
DR   IntAct; Q4G163; 4.
DR   MINT; Q4G163; -.
DR   STRING; 9606.ENSP00000403293; -.
DR   GlyCosmos; Q4G163; 1 site, 1 glycan.
DR   GlyGen; Q4G163; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q4G163; -.
DR   PhosphoSitePlus; Q4G163; -.
DR   BioMuta; FBXO43; -.
DR   DMDM; 152031603; -.
DR   jPOST; Q4G163; -.
DR   MassIVE; Q4G163; -.
DR   PaxDb; 9606-ENSP00000403293; -.
DR   PeptideAtlas; Q4G163; -.
DR   ProteomicsDB; 62156; -.
DR   Antibodypedia; 6910; 122 antibodies from 32 providers.
DR   DNASU; 286151; -.
DR   Ensembl; ENST00000428847.3; ENSP00000403293.2; ENSG00000156509.14.
DR   GeneID; 286151; -.
DR   KEGG; hsa:286151; -.
DR   MANE-Select; ENST00000428847.3; ENSP00000403293.2; NM_001029860.4; NP_001025031.2.
DR   UCSC; uc003yjd.4; human.
DR   AGR; HGNC:28521; -.
DR   ClinPGx; PA134913061; -.
DR   CTD; 286151; -.
DR   DisGeNET; 286151; -.
DR   GeneCards; FBXO43; -.
DR   HGNC; HGNC:28521; FBXO43.
DR   HPA; ENSG00000156509; Tissue enriched (testis).
DR   MalaCards; FBXO43; -.
DR   MIM; 609110; gene.
DR   MIM; 619696; phenotype.
DR   MIM; 619697; phenotype.
DR   OpenTargets; ENSG00000156509; -.
DR   Orphanet; 399805; Male infertility with azoospermia or oligozoospermia due to single gene mutation.
DR   VEuPathDB; HostDB:ENSG00000156509; -.
DR   eggNOG; ENOG502QRSQ; Eukaryota.
DR   GeneTree; ENSGT00530000063692; -.
DR   HOGENOM; CLU_029091_0_0_1; -.
DR   InParanoid; Q4G163; -.
DR   OMA; FCILCLH; -.
DR   OrthoDB; 9984940at2759; -.
DR   PAN-GO; Q4G163; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; Q4G163; -.
DR   PathwayCommons; Q4G163; -.
DR   SignaLink; Q4G163; -.
DR   SIGNOR; Q4G163; -.
DR   UniPathway; UPA00143; -.
DR   Agora; ENSG00000156509; -.
DR   BioGRID-ORCS; 286151; 18 hits in 1197 CRISPR screens.
DR   ChiTaRS; FBXO43; human.
DR   GenomeRNAi; 286151; -.
DR   Pharos; Q4G163; Tbio.
DR   PRO; PR:Q4G163; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; Q4G163; protein.
DR   Bgee; ENSG00000156509; Expressed in secondary oocyte and 117 other cell types or tissues.
DR   ExpressionAtlas; Q4G163; baseline and differential.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW.
DR   GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
DR   GO; GO:0051321; P:meiotic cell cycle; IEA:UniProtKB-KW.
DR   GO; GO:0010948; P:negative regulation of cell cycle process; IMP:UniProtKB.
DR   GO; GO:0045835; P:negative regulation of meiotic nuclear division; IBA:GO_Central.
DR   GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR   GO; GO:0007088; P:regulation of mitotic nuclear division; IBA:GO_Central.
DR   GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; NAS:ComplexPortal.
DR   CDD; cd20365; BRcat_RBR_FBXO43; 1.
DR   CDD; cd22171; F-box_FBXO43; 1.
DR   FunFam; 2.20.25.20:FF:000006; F-box only protein 5; 1.
DR   FunFam; 1.20.1280.50:FF:000046; F-box protein 43; 1.
DR   Gene3D; 1.20.1280.50; -; 1.
DR   Gene3D; 2.20.25.20; -; 1.
DR   InterPro; IPR001810; F-box_dom.
DR   InterPro; IPR047147; FBX5_43.
DR   InterPro; IPR002867; IBR_dom.
DR   InterPro; IPR044064; ZF_ZBR.
DR   PANTHER; PTHR15493:SF1; F-BOX ONLY PROTEIN 43; 1.
DR   PANTHER; PTHR15493; F-BOX ONLY PROTEIN 5 AND 43; 1.
DR   Pfam; PF00646; F-box; 1.
DR   Pfam; PF28485; FBXO43_HTH; 1.
DR   SMART; SM00647; IBR; 1.
DR   SUPFAM; SSF57850; RING/U-box; 1.
DR   PROSITE; PS51872; ZF_ZBR; 1.
PE   1: Evidence at protein level;
KW   Disease variant; Meiosis; Metal-binding; Phosphoprotein;
KW   Proteomics identification; Reference proteome; Ubl conjugation;
KW   Ubl conjugation pathway; Zinc; Zinc-finger.
FT   CHAIN           1..708
FT                   /note="F-box only protein 43"
FT                   /id="PRO_0000247233"
FT   DOMAIN          490..547
FT                   /note="F-box"
FT   ZN_FING         636..684
FT                   /note="ZBR-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   REGION          35..55
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          320..426
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          682..708
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        327..337
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        374..385
FT                   /note="Basic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        399..411
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         640
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         643
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         658
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         663
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         668
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         671
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         676
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   BINDING         681
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01220"
FT   MOD_RES         76
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000305|PubMed:15753281"
FT   MOD_RES         234
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:16407128"
FT   MOD_RES         334
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000305|PubMed:15753281"
FT   VARIANT         98
FT                   /note="E -> G (in SPGF64; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:30878252"
FT                   /id="VAR_086815"
FT   VARIANT         139
FT                   /note="P -> L (in dbSNP:rs2279102)"
FT                   /id="VAR_061168"
FT   VARIANT         139
FT                   /note="P -> R (in dbSNP:rs2279102)"
FT                   /id="VAR_061169"
FT   VARIANT         149
FT                   /note="G -> A (in SPGF64; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:30878252"
FT                   /id="VAR_086816"
FT   VARIANT         250
FT                   /note="I -> L (in SPGF64; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:30878252"
FT                   /id="VAR_086817"
FT   VARIANT         583..708
FT                   /note="Missing (in OZEMA12 and SPGF64; reduced protein
FT                   abundance; failed to significantly upregulate CCNB1; the
FT                   variant does not rescue the mouse knockdown oocyte
FT                   phenotype compared to wild-type protein)"
FT                   /evidence="ECO:0000269|PubMed:34052850,
FT                   ECO:0000269|PubMed:34595750"
FT                   /id="VAR_086818"
FT   VARIANT         594
FT                   /note="E -> G (in SPGF64; uncertain significance;
FT                   dbSNP:rs1814398420)"
FT                   /evidence="ECO:0000269|PubMed:30878252"
FT                   /id="VAR_086819"
FT   VARIANT         664
FT                   /note="G -> D (in SPGF64; uncertain significance;
FT                   dbSNP:rs954702094)"
FT                   /evidence="ECO:0000269|PubMed:30878252"
FT                   /id="VAR_086820"
FT   MUTAGEN         75..76
FT                   /note="DS->AA: Impairs ubiquitination and degradation in
FT                   response to calcium."
FT                   /evidence="ECO:0000269|PubMed:15753281"
FT   MUTAGEN         333..334
FT                   /note="DS->AA: Impairs ubiquitination and degradation in
FT                   response to calcium."
FT                   /evidence="ECO:0000269|PubMed:15753281"
SQ   SEQUENCE   708 AA;  78402 MW;  E42A358AE7BD29D1 CRC64;
     MSFKDKDERI SCLEAYVTLT SKSSRFTDET EILKMSQRHS GQAGTEAGNG ADSPPIVNSK
     YSTFRDFCST SSFQDSGYNE LKSCSFDNID KEYLGKKEKG PTLLYEHPET SGLGLTHPLE
     SPTQKKKCIL PRKEKDKTPE LCETPKISGK KCLPRRRLNV SFALLKGDFE SQNSSLESSI
     SQVINLEKNI PSSASGFSRA NNFSPLVTST LKTEEVTSCS QKLRLNFSQQ KTSTIDDSKD
     DCSLFEVECI SPIQGNNFKD SITHDFSDSS LCINDENACP ELLGSSVSGT TCGTDEDIFV
     TPISNLVANI RFNASQILSP SPEVRGSIST PEDSGFNSLS LEKSEDSLSD QEGSFQELLQ
     KHKGTPKVGD TIRKTRHLGR SRRLSTLREQ SSQSETEEEK QIVHPDSEKR AAAASAISEG
     QLSSDESGDL TFSLKNLSKT PALQLVHELF MKSKRKRLQE NSGHEFLEQG DGEKIAVLQC
     ILAGLIGKKM GIEKLDILTE LKYRNLKHIL AMVLESLTAE SLCSVWKVSR NWREIVVQDK
     NANRRRKFYI TQLKTDSEGA VLNVEDAATR LQLLNRSALR SVQAQARIPG SQREQGSTLS
     PWGEVLTPLA SSSVTHLSSK QEEYVKVAKT LFTDEALKPC PRCQSPAKYQ PYKKRGLCSR
     TACGFDFCVL CLCAYHGSEE CSRGAAKPRN RKDALPGSAQ SKRNLKRL
//