ID KLH25_HUMAN Reviewed; 589 AA.
AC Q9H0H3; B2RDH2; B3KRT7;
DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 27-MAR-2024, entry version 164.
DE RecName: Full=Kelch-like protein 25 {ECO:0000305};
DE AltName: Full=Ectoderm-neural cortex protein 2 {ECO:0000303|Ref.1};
DE Short=ENC-2 {ECO:0000303|Ref.1};
GN Name=KLHL25 {ECO:0000303|PubMed:22578813, ECO:0000312|HGNC:HGNC:25732};
GN Synonyms=ENC2 {ECO:0000303|Ref.1};
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].
RA Corcoran M.M.;
RT "ENC2 a member of the BTB/POZ KELCH protein family.";
RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ILE-250.
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 GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [7]
RP FUNCTION, PATHWAY, AND IDENTIFICATION IN A BCR (BTB-CUL3-RBX1) E3 UBIQUITIN
RP LIGASE COMPLEX.
RX PubMed=22578813; DOI=10.1016/j.molcel.2012.04.004;
RA Yanagiya A., Suyama E., Adachi H., Svitkin Y.V., Aza-Blanc P., Imataka H.,
RA Mikami S., Martineau Y., Ronai Z.A., Sonenberg N.;
RT "Translational homeostasis via the mRNA cap-binding protein, eIF4E.";
RL Mol. Cell 46:847-858(2012).
RN [8]
RP FUNCTION, PATHWAY, AND IDENTIFICATION IN A BCR (BTB-CUL3-RBX1) E3 UBIQUITIN
RP LIGASE COMPLEX.
RX PubMed=27664236; DOI=10.1101/gad.283283.116;
RA Zhang C., Liu J., Huang G., Zhao Y., Yue X., Wu H., Li J., Zhu J., Shen Z.,
RA Haffty B.G., Hu W., Feng Z.;
RT "Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit
RT lipid synthesis and tumor progression.";
RL Genes Dev. 30:1956-1970(2016).
RN [9]
RP FUNCTION, AND PATHWAY.
RX PubMed=34491895; DOI=10.7554/elife.62394;
RA Tian M., Hao F., Jin X., Sun X., Jiang Y., Wang Y., Li D., Chang T.,
RA Zou Y., Peng P., Xia C., Liu J., Li Y., Wang P., Feng Y., Wei M.;
RT "ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid
RT metabolism to facilitate iTreg differentiation.";
RL Elife 10:0-0(2021).
CC -!- FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3
CC ubiquitin ligase complex involved in various processes, such as
CC translation homeostasis and lipid synthesis (PubMed:22578813,
CC PubMed:27664236, PubMed:34491895). The BCR(KLHL25) ubiquitin ligase
CC complex acts by mediating ubiquitination of hypophosphorylated EIF4EBP1
CC (4E-BP1): ubiquitination and subsequent degradation of
CC hypophosphorylated EIF4EBP1 (4E-BP1) probably serves as a homeostatic
CC mechanism to maintain translation and prevent eIF4E inhibition when
CC eIF4E levels are low (PubMed:22578813). The BCR(KLHL25) complex does
CC not target EIF4EBP1 (4E-BP1) when it is hyperphosphorylated or
CC associated with eIF4E (PubMed:22578813). The BCR(KLHL25) complex also
CC acts as a regulator of lipid synthesis by mediating ubiquitination and
CC degradation of ACLY, thereby inhibiting lipid synthesis
CC (PubMed:27664236, PubMed:34491895). BCR(KLHL25)-mediated degradation of
CC ACLY promotes fatty acid oxidation and is required for differentiation
CC of inducible regulatory T (iTreg) cells (PubMed:34491895).
CC {ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:27664236,
CC ECO:0000269|PubMed:34491895}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:22578813, ECO:0000269|PubMed:27664236,
CC ECO:0000269|PubMed:34491895}.
CC -!- SUBUNIT: Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at
CC least composed of CUL3, KLHL25 and RBX1. {ECO:0000269|PubMed:22578813,
CC ECO:0000269|PubMed:27664236}.
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DR EMBL; AY764034; AAV51405.1; -; mRNA.
DR EMBL; AL136796; CAB66730.1; -; mRNA.
DR EMBL; AK092231; BAG52499.1; -; mRNA.
DR EMBL; AK315541; BAG37919.1; -; mRNA.
DR EMBL; AC021739; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC028100; AAH28100.1; -; mRNA.
DR CCDS; CCDS10339.1; -.
DR RefSeq; NP_071925.2; NM_022480.3.
DR AlphaFoldDB; Q9H0H3; -.
DR SMR; Q9H0H3; -.
DR BioGRID; 122162; 18.
DR ComplexPortal; CPX-8126; CRL3 E3 ubiquitin ligase complex, KLHL25 variant.
DR CORUM; Q9H0H3; -.
DR IntAct; Q9H0H3; 14.
DR MINT; Q9H0H3; -.
DR STRING; 9606.ENSP00000336800; -.
DR iPTMnet; Q9H0H3; -.
DR PhosphoSitePlus; Q9H0H3; -.
DR BioMuta; KLHL25; -.
DR DMDM; 74733525; -.
DR EPD; Q9H0H3; -.
DR jPOST; Q9H0H3; -.
DR MassIVE; Q9H0H3; -.
DR MaxQB; Q9H0H3; -.
DR PaxDb; 9606-ENSP00000336800; -.
DR PeptideAtlas; Q9H0H3; -.
DR ProteomicsDB; 80278; -.
DR Pumba; Q9H0H3; -.
DR Antibodypedia; 15613; 252 antibodies from 29 providers.
DR DNASU; 64410; -.
DR Ensembl; ENST00000337975.6; ENSP00000336800.5; ENSG00000183655.13.
DR GeneID; 64410; -.
DR KEGG; hsa:64410; -.
DR MANE-Select; ENST00000337975.6; ENSP00000336800.5; NM_022480.4; NP_071925.2.
DR UCSC; uc002bly.5; human.
DR AGR; HGNC:25732; -.
DR CTD; 64410; -.
DR DisGeNET; 64410; -.
DR GeneCards; KLHL25; -.
DR HGNC; HGNC:25732; KLHL25.
DR HPA; ENSG00000183655; Low tissue specificity.
DR MIM; 619893; gene.
DR neXtProt; NX_Q9H0H3; -.
DR OpenTargets; ENSG00000183655; -.
DR PharmGKB; PA142671577; -.
DR VEuPathDB; HostDB:ENSG00000183655; -.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00950000182983; -.
DR HOGENOM; CLU_004253_14_6_1; -.
DR InParanoid; Q9H0H3; -.
DR OMA; SHLNTMR; -.
DR OrthoDB; 5472491at2759; -.
DR PhylomeDB; Q9H0H3; -.
DR TreeFam; TF329218; -.
DR PathwayCommons; Q9H0H3; -.
DR Reactome; R-HSA-8951664; Neddylation.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q9H0H3; -.
DR SIGNOR; Q9H0H3; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 64410; 11 hits in 1189 CRISPR screens.
DR ChiTaRS; KLHL25; human.
DR GeneWiki; KLHL25; -.
DR GenomeRNAi; 64410; -.
DR Pharos; Q9H0H3; Tbio.
DR PRO; PR:Q9H0H3; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q9H0H3; Protein.
DR Bgee; ENSG00000183655; Expressed in ventricular zone and 114 other cell types or tissues.
DR Genevisible; Q9H0H3; HS.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:LIFEdb.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; IDA:UniProtKB.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0032831; P:positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; IDA:UniProtKB.
DR GO; GO:0046321; P:positive regulation of fatty acid oxidation; IDA:UniProt.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0006446; P:regulation of translational initiation; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR CDD; cd18514; BACK_KLHL25_ENC2; 1.
DR CDD; cd18254; BTB_POZ_KLHL25; 1.
DR Gene3D; 1.25.40.420; -; 1.
DR Gene3D; 2.120.10.80; Kelch-type beta propeller; 2.
DR InterPro; IPR011705; BACK.
DR InterPro; IPR017096; BTB-kelch_protein.
DR InterPro; IPR000210; BTB/POZ_dom.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR InterPro; IPR006652; Kelch_1.
DR InterPro; IPR030565; KLHL25_BTB_POZ_dom.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR PANTHER; PTHR24412; KELCH PROTEIN; 1.
DR PANTHER; PTHR24412:SF488; KELCH-LIKE PROTEIN 20; 1.
DR Pfam; PF07707; BACK; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF01344; Kelch_1; 5.
DR PIRSF; PIRSF037037; Kelch-like_protein_gigaxonin; 1.
DR SMART; SM00875; BACK; 1.
DR SMART; SM00225; BTB; 1.
DR SMART; SM00612; Kelch; 6.
DR SUPFAM; SSF117281; Kelch motif; 1.
DR SUPFAM; SSF54695; POZ domain; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW Kelch repeat; Reference proteome; Repeat; Translation regulation;
KW Ubl conjugation pathway.
FT CHAIN 1..589
FT /note="Kelch-like protein 25"
FT /id="PRO_0000272308"
FT DOMAIN 46..114
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 149..250
FT /note="BACK"
FT REPEAT 296..340
FT /note="Kelch 1"
FT REPEAT 341..388
FT /note="Kelch 2"
FT REPEAT 389..444
FT /note="Kelch 3"
FT REPEAT 446..492
FT /note="Kelch 4"
FT REPEAT 494..538
FT /note="Kelch 5"
FT REPEAT 539..585
FT /note="Kelch 6"
FT VARIANT 250
FT /note="V -> I (in dbSNP:rs35582838)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_050041"
FT VARIANT 257
FT /note="M -> L (in dbSNP:rs36031133)"
FT /id="VAR_050042"
FT CONFLICT 320
FT /note="I -> T (in Ref. 3; BAG37919)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 589 AA; 65923 MW; 411795EF2C616BF4 CRC64;
MSVSVHETRK SRSSTGSMNV TLFHKASHPD CVLAHLNTLR KHCMFTDVTL WAGDRAFPCH
RAVLAASSRY FEAMFSHGLR ESRDDTVNFQ DNLHPEVLEL LLDFAYSSRI AINEENAESL
LEAGDMLQFH DVRDAAAEFL EKNLFPSNCL GMMLLSDAHQ CRRLYEFSWR MCLVHFETVR
QSEDFNSLSK DTLLDLISSD ELETEDERVV FEAILQWVKH DLEPRKVHLP ELLRSVRLAL
LPSDCLQEAV SSEALLMADE RTKLIMDEAL RCKTRILQND GVVTSPCARP RKAGHTLLIL
GGQTFMCDKI YQVDHKAKEI IPKADLPSPR KEFSASAIGC KVYVTGGRGS ENGVSKDVWV
YDTVHEEWSK AAPMLIARFG HGSAELENCL YVVGGHTSLA GVFPASPSVS LKQVEKYDPG
ANKWMMVAPL RDGVSNAAVV SAKLKLFVFG GTSIHRDMVS KVQCYDPSEN RWTIKAECPQ
PWRYTAAAVL GSQIFIMGGD TEFTAASAYR FDCETNQWTR IGDMTAKRMS CHALASGNKL
YVVGGYFGTQ RCKTLDCYDP TSDTWNCITT VPYSLIPTAF VSTWKHLPA
//
