KLHL3_MOUSE
ID KLHL3_MOUSE Reviewed; 587 AA.
AC E0CZ16; F7A5U9; I6L891;
DT 16-MAY-2012, integrated into UniProtKB/Swiss-Prot.
DT 16-MAY-2012, sequence version 2.
DT 03-AUG-2022, entry version 78.
DE RecName: Full=Kelch-like protein 3;
GN Name=Klhl3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP TISSUE SPECIFICITY.
RX PubMed=22266938; DOI=10.1038/nature10814;
RA Boyden L.M., Choi M., Choate K.A., Nelson-Williams C.J., Farhi A.,
RA Toka H.R., Tikhonova I.R., Bjornson R., Mane S.M., Colussi G., Lebel M.,
RA Gordon R.D., Semmekrot B.A., Poujol A., Valimaki M.J., De Ferrari M.E.,
RA Sanjad S.A., Gutkin M., Karet F.E., Tucci J.R., Stockigt J.R.,
RA Keppler-Noreuil K.M., Porter C.C., Anand S.K., Whiteford M.L., Davis I.D.,
RA Dewar S.B., Bettinelli A., Fadrowski J.J., Belsha C.W., Hunley T.E.,
RA Nelson R.D., Trachtman H., Cole T.R., Pinsk M., Bockenhauer D., Shenoy M.,
RA Vaidyanathan P., Foreman J.W., Rasoulpour M., Thameem F.,
RA Al-Shahrouri H.Z., Radhakrishnan J., Gharavi A.G., Goilav B., Lifton R.P.;
RT "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte
RT abnormalities.";
RL Nature 482:98-102(2012).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=22406640; DOI=10.1038/ng.2218;
RA Louis-Dit-Picard H., Barc J., Trujillano D., Miserey-Lenkei S.,
RA Bouatia-Naji N., Pylypenko O., Beaurain G., Bonnefond A., Sand O.,
RA Simian C., Vidal-Petiot E., Soukaseum C., Mandet C., Broux F., Chabre O.,
RA Delahousse M., Esnault V., Fiquet B., Houillier P., Bagnis C.I., Koenig J.,
RA Konrad M., Landais P., Mourani C., Niaudet P., Probst V., Thauvin C.,
RA Unwin R.J., Soroka S.D., Ehret G., Ossowski S., Caulfield M., Bruneval P.,
RA Estivill X., Froguel P., Hadchouel J., Schott J.J., Jeunemaitre X.;
RT "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion
RT transport in the distal nephron.";
RL Nat. Genet. 44:456-460(2012).
RN [4]
RP FUNCTION, AND INTERACTION WITH CLDN8.
RX PubMed=25831548; DOI=10.1073/pnas.1421441112;
RA Gong Y., Wang J., Yang J., Gonzales E., Perez R., Hou J.;
RT "KLHL3 regulates paracellular chloride transport in the kidney by
RT ubiquitination of claudin-8.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:4340-4345(2015).
RN [5]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=28052936; DOI=10.1128/mcb.00508-16;
RA Sasaki E., Susa K., Mori T., Isobe K., Araki Y., Inoue Y., Yoshizaki Y.,
RA Ando F., Mori Y., Mandai S., Zeniya M., Takahashi D., Nomura N., Rai T.,
RA Uchida S., Sohara E.;
RT "KLHL3 knockout mice reveal the physiological role of KLHL3 and the
RT pathophysiology of pseudohypoaldosteronism type II caused by mutant
RT KLHL3.";
RL Mol. Cell. Biol. 37:0-0(2017).
CC -!- FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3
CC ubiquitin ligase complex that acts as a regulator of ion transport in
CC the distal nephron (PubMed:25831548, PubMed:28052936). The BCR(KLHL3)
CC complex acts by mediating ubiquitination of WNK4, an inhibitor of
CC potassium channel KCNJ1, leading to WNK4 degradation (By similarity).
CC The BCR(KLHL3) complex also mediates ubiquitination and degradation of
CC CLDN8, a tight-junction protein required for paracellular chloride
CC transport in the kidney (PubMed:25831548).
CC {ECO:0000250|UniProtKB:Q9UH77, ECO:0000269|PubMed:25831548,
CC ECO:0000269|PubMed:28052936}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q9UH77}.
CC -!- SUBUNIT: Homodimer. Component of the BCR(KLHL3) E3 ubiquitin ligase
CC complex, at least composed of CUL3 and KLHL3 and RBX1 (By similarity).
CC Interacts with SLC12A3 (By similarity). Interacts with WNK1 and WNK4
CC (By similarity). Interacts with CLDN8 (PubMed:25831548).
CC {ECO:0000250|UniProtKB:Q9UH77, ECO:0000269|PubMed:25831548}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC {ECO:0000250|UniProtKB:Q9UH77}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9UH77}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=E0CZ16-1; Sequence=Displayed;
CC Name=2;
CC IsoId=E0CZ16-2; Sequence=VSP_053297;
CC -!- TISSUE SPECIFICITY: Present at high level in brain and kidney (at
CC protein level) (PubMed:28052936). Weakly expressed in other tissues
CC (PubMed:28052936). In kidney, predominantly localizes to the distal
CC convoluted tubule (DCT) and collecting duct, with apical localization
CC in the DCT (at protein level) (PubMed:22266938, PubMed:22406640).
CC {ECO:0000269|PubMed:22266938, ECO:0000269|PubMed:22406640,
CC ECO:0000269|PubMed:28052936}.
CC -!- PTM: Phosphorylation at Ser-433 by PKA decreases the interaction with
CC WNK4, Leading to inhibit WNK4 degradation by the BCR(KLHL3) complex.
CC Phosphorylation at Ser-433 is increased by insulin.
CC {ECO:0000250|UniProtKB:Q9UH77}.
CC -!- DISRUPTION PHENOTYPE: Mice display pseudohypoaldosteronism type II
CC (PHA2)-like phenotype, such as salt-sensitive hypertension
CC (PubMed:28052936). In kidney, increased level of Wnk1 and Wnk4 kinases
CC is observed, while Wnk1 and Wnk4 levels are unchanged in other tissues
CC (PubMed:28052936). {ECO:0000269|PubMed:28052936}.
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DR EMBL; AC142258; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC165251; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS88463.1; -. [E0CZ16-1]
DR RefSeq; NP_001182004.1; NM_001195075.1.
DR AlphaFoldDB; E0CZ16; -.
DR SMR; E0CZ16; -.
DR BioGRID; 437092; 8.
DR IntAct; E0CZ16; 1.
DR STRING; 10090.ENSMUSP00000089173; -.
DR iPTMnet; E0CZ16; -.
DR PhosphoSitePlus; E0CZ16; -.
DR PaxDb; E0CZ16; -.
DR PRIDE; E0CZ16; -.
DR ProteomicsDB; 263631; -. [E0CZ16-1]
DR ProteomicsDB; 263632; -. [E0CZ16-2]
DR Antibodypedia; 14776; 269 antibodies from 28 providers.
DR Ensembl; ENSMUST00000160860; ENSMUSP00000123701; ENSMUSG00000014164. [E0CZ16-1]
DR UCSC; uc011zal.1; mouse. [E0CZ16-2]
DR MGI; MGI:2445185; Klhl3.
DR VEuPathDB; HostDB:ENSMUSG00000014164; -.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000157891; -.
DR InParanoid; E0CZ16; -.
DR OMA; NHKTNEW; -.
DR OrthoDB; 635140at2759; -.
DR TreeFam; TF329218; -.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 100503085; 4 hits in 71 CRISPR screens.
DR PRO; PR:E0CZ16; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; E0CZ16; protein.
DR Bgee; ENSMUSG00000014164; Expressed in dentate gyrus of hippocampal formation granule cell and 60 other tissues.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; ISS:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0003779; F:actin binding; IEA:UniProtKB-KW.
DR GO; GO:0097602; F:cullin family protein binding; ISO:MGI.
DR GO; GO:0072156; P:distal tubule morphogenesis; ISS:UniProtKB.
DR GO; GO:0010467; P:gene expression; IDA:MGI.
DR GO; GO:0050801; P:ion homeostasis; IMP:MGI.
DR GO; GO:0055075; P:potassium ion homeostasis; IMP:MGI.
DR GO; GO:0030163; P:protein catabolic process; IMP:MGI.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IMP:MGI.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:MGI.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0070293; P:renal absorption; IMP:MGI.
DR GO; GO:0070294; P:renal sodium ion absorption; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR Gene3D; 2.120.10.80; -; 1.
DR Gene3D; 3.30.710.10; -; 1.
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; IPR030578; KLHL3.
DR InterPro; IPR011041; Quinoprot_gluc/sorb_DH.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR PANTHER; PTHR24412:SF179; PTHR24412:SF179; 1.
DR Pfam; PF07707; BACK; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF01344; Kelch_1; 6.
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; SSF117281; 1.
DR SUPFAM; SSF50952; SSF50952; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW Actin-binding; Alternative splicing; Cytoplasm; Cytoskeleton; Kelch repeat;
KW Phosphoprotein; Reference proteome; Repeat; Ubl conjugation pathway.
FT CHAIN 1..587
FT /note="Kelch-like protein 3"
FT /id="PRO_0000417531"
FT DOMAIN 50..117
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 152..254
FT /note="BACK"
FT REPEAT 302..347
FT /note="Kelch 1"
FT REPEAT 348..394
FT /note="Kelch 2"
FT REPEAT 396..441
FT /note="Kelch 3"
FT REPEAT 442..490
FT /note="Kelch 4"
FT REPEAT 491..537
FT /note="Kelch 5"
FT REPEAT 539..585
FT /note="Kelch 6"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 295
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UH77"
FT MOD_RES 375
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UH77"
FT MOD_RES 376
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UH77"
FT MOD_RES 433
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UH77"
FT VAR_SEQ 1..4
FT /note="MEGE -> MAYYIMIPCQVGKRGHRLWTWTRVAARINVALCFVGGESAWFLL
FT VSRLTSASGGKGL (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_053297"
SQ SEQUENCE 587 AA; 64922 MW; 96A7B7D0B80E11E9 CRC64;
MEGESVKPSP QPTAQAEDEE KNRRTVTVNA AHMGKAFKVM NELRSKRLLC DVMIVAEDVE
VEAHRVVLAA CSPYFCAMFT GDMSESKAKK IEIKDVDGQT LSKLIDYIYT AEIEVTEENV
QVLLPAASLL QLMDVRQNCC DFLQSQLHPT NCLGIRAFAD VHTCTDLLQQ ANAYAEQHFP
EVMLGEEFLS LSLDQVCSLI SSDKLTVSSE EKVFEAVISW INYEKETRLD HMAKLMEHVR
LPLLPRDYLV QTVEEEALIK NNNTCKDFLI EAMKYHLLPL DQRLLIKNPR TKPRTPVSLP
KVMIVVGGQA PKAIRSVECY DFEEGRWDQI AELPSRRCRA GVVFMAGHVY AVGGFNGSLR
VRTVDVYDGV KDQWTSIASM QERRSTLGAA VLNDLLYAVG GFDGSTGLAS VEAYSYKTNE
WFFVAPMNTR RSSVGVGVVE GKLYAVGGYD GASRQCLSTV EQYNPATNEW IYVADMSTRR
SGAGVGVLSG QLYATGGHDG PLVRKSVEVY DPGTNTWKQV ADMNMCRRNA GVCAVNGLLY
VVGGDDGSCN LASVEYYNPV TDKWTLLPTN MSTGRSYAGV AVIHKSL
