KLHL3_HUMAN
ID KLHL3_HUMAN Reviewed; 587 AA.
AC Q9UH77; B2RBK7; Q9UH75; Q9UH76; Q9ULU0; Q9Y6V6;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 2.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=Kelch-like protein 3;
GN Name=KLHL3 {ECO:0000303|PubMed:10843806, ECO:0000312|HGNC:HGNC:6354};
GN Synonyms=KIAA1129 {ECO:0000303|PubMed:10574461};
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] (ISOFORMS A; B AND C), AND ALTERNATIVE SPLICING.
RC TISSUE=Bone marrow;
RX PubMed=10843806; DOI=10.1006/geno.2000.6181;
RA Lai F., Orelli B.J., Till B.G., Godley L.A., Fernald A.A., Pamintuan L.,
RA Le Beau M.M.;
RT "Molecular characterization of KLHL3, a human homologue of the Drosophila
RT kelch gene.";
RL Genomics 66:65-75(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC TISSUE=Brain;
RX PubMed=10574461; DOI=10.1093/dnares/6.5.329;
RA Hirosawa M., Nagase T., Ishikawa K., Kikuno R., Nomura N., Ohara O.;
RT "Characterization of cDNA clones selected by the GeneMark analysis from
RT size-fractionated cDNA libraries from human brain.";
RL DNA Res. 6:329-336(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC TISSUE=Kidney;
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=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION AS AN E3 UBIQUITIN-PROTEIN LIGASE, AND INTERACTION WITH CUL3.
RX PubMed=14528312; DOI=10.1038/ncb1056;
RA Furukawa M., He Y.J., Borchers C., Xiong Y.;
RT "Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin
RT ligases.";
RL Nat. Cell Biol. 5:1001-1007(2003).
RN [7]
RP FUNCTION, INTERACTION WITH CUL3; WNK1 AND WNK4, AND CHARACTERIZATION OF
RP VARIANTS PHA2D GLU-77; VAL-78; ALA-85; PHE-164; ARG-309; VAL-340; GLN-384;
RP PRO-387; LEU-410; ASN-432; ASN-433; THR-494; HIS-528; CYS-528 AND LYS-529.
RX PubMed=23387299; DOI=10.1042/bj20121903;
RA Ohta A., Schumacher F.R., Mehellou Y., Johnson C., Knebel A.,
RA Macartney T.J., Wood N.T., Alessi D.R., Kurz T.;
RT "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome
RT interacts with and ubiquitylates WNK isoforms: disease-causing mutations in
RT KLHL3 and WNK4 disrupt interaction.";
RL Biochem. J. 451:111-122(2013).
RN [8]
RP FUNCTION, IDENTIFICATION IN A BCR (BTB-CUL3-RBX1) E3 UBIQUITIN LIGASE
RP COMPLEX, INTERACTION WITH WNK4 AND CUL3, AND CHARACTERIZATION OF VARIANT
RP PHA2D HIS-528.
RX PubMed=23453970; DOI=10.1016/j.celrep.2013.02.024;
RA Wakabayashi M., Mori T., Isobe K., Sohara E., Susa K., Araki Y., Chiga M.,
RA Kikuchi E., Nomura N., Mori Y., Matsuo H., Murata T., Nomura S., Asano T.,
RA Kawaguchi H., Nonoyama S., Rai T., Sasaki S., Uchida S.;
RT "Impaired KLHL3-mediated ubiquitination of WNK4 causes human
RT hypertension.";
RL Cell Rep. 3:858-868(2013).
RN [9]
RP FUNCTION, INTERACTION WITH WNK4, AND CHARACTERIZATION OF VARIANTS PHA2D
RP GLU-77; PHE-164; ARG-309; PRO-387 AND CYS-528.
RX PubMed=23665031; DOI=10.1016/j.febslet.2013.04.032;
RA Wu G., Peng J.B.;
RT "Disease-causing mutations in KLHL3 impair its effect on WNK4
RT degradation.";
RL FEBS Lett. 587:1717-1722(2013).
RN [10]
RP FUNCTION, IDENTIFICATION IN A BCR (BTB-CUL3-RBX1) E3 UBIQUITIN LIGASE
RP COMPLEX, INTERACTION WITH WNK1; WNK4 AND CUL3, AND CHARACTERIZATION OF
RP VARIANT PHA2D HIS-528.
RX PubMed=23576762; DOI=10.1073/pnas.1304592110;
RA Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.;
RT "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via
RT ubiquitination and degradation of WNK4.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013).
RN [11]
RP PHOSPHORYLATION AT SER-10; THR-295; THR-375; SER-376 AND SER-433,
RP INTERACTION WITH WNK4, CHARACTERIZATION OF VARIANT PHA2D GLY-433, AND
RP MUTAGENESIS OF SER-433.
RX PubMed=26435498; DOI=10.1016/j.bbrc.2015.09.184;
RA Yoshizaki Y., Mori Y., Tsuzaki Y., Mori T., Nomura N., Wakabayashi M.,
RA Takahashi D., Zeniya M., Kikuchi E., Araki Y., Ando F., Isobe K.,
RA Nishida H., Ohta A., Susa K., Inoue Y., Chiga M., Rai T., Sasaki S.,
RA Uchida S., Sohara E.;
RT "Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3.";
RL Biochem. Biophys. Res. Commun. 467:229-234(2015).
RN [12]
RP SUBUNIT, VARIANT PHA2D HIS-528, AND CHARACTERIZATION OF VARIANT PHA2D
RP HIS-528.
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).
RN [13]
RP PHOSPHORYLATION AT SER-433, AND INTERACTION WITH WNK4.
RX PubMed=27727489; DOI=10.1002/pro.3063;
RA Wang L., Peng J.B.;
RT "Phosphorylation of KLHL3 at serine 433 impairs its interaction with the
RT acidic motif of WNK4: a molecular dynamics study.";
RL Protein Sci. 26:163-173(2017).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (3.51 ANGSTROMS) OF 24-276 IN COMPLEX WITH CUL3.
RX PubMed=23573258; DOI=10.1371/journal.pone.0060445;
RA Ji A.X., Prive G.G.;
RT "Crystal structure of KLHL3 in complex with Cullin3.";
RL PLoS ONE 8:E60445-E60445(2013).
RN [15]
RP VARIANTS PHA2D GLU-77; VAL-78; ALA-85; PHE-164; ARG-309; CYS-322; ILE-336;
RP VAL-340; GLN-384; PRO-387; LEU-410; THR-427; GLN-431; ASN-432; ASN-433;
RP THR-494; THR-501; HIS-528; CYS-528; CYS-557 AND TRP-575, AND VARIANT
RP ILE-438.
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 [16]
RP VARIANTS PHA2D GLY-228; MET-361; TRP-362; TRP-384; VAL-398; LEU-410;
RP LEU-426; ASN-432; GLY-433; VAL-500; HIS-528; CYS-528 AND LYS-529, FUNCTION,
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH SLC12A3.
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 [17]
RP VARIANT PHA2D PRO-387.
RX PubMed=27780982; DOI=10.1297/cpe.25.127;
RA Mitani M., Furuichi M., Narumi S., Hasegawa T., Chiga M., Uchida S.,
RA Sato S.;
RT "A patient with pseudohypoaldosteronism type II complicated by congenital
RT hypopituitarism carrying a KLHL3 mutation.";
RL Clin. Pediatr. Endocrinol. 25:127-134(2016).
RN [18]
RP VARIANT PHA2D TYR-498.
RX PubMed=27026694; DOI=10.1093/qjmed/hcw043;
RA Kelly D., Rodzlan M.R., Jeunemaitre X., Wall C.;
RT "A novel mutation in KLHL3 gene causes familial hyperkalemic
RT hypertension.";
RL QJM 109:487-488(2016).
RN [19]
RP VARIANTS PHA2D ARG-309 AND LEU-553.
RX PubMed=28511177; DOI=10.1159/000475825;
RA Kliuk-Ben Bassat O., Carmon V., Hanukoglu A., Ganon L., Massalha E.,
RA Holtzman E.J., Farfel Z., Mayan H.;
RT "Familial hyperkalemia and hypertension (FHHt) and KLHL3: Description of a
RT family with a new recessive mutation (S553L) compared to a family with a
RT dominant mutation, Q309R, with analysis of urinary sodium chloride
RT cotransporter.";
RL Nephron 137:77-84(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:14528312, PubMed:22406640, PubMed:23387299,
CC PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3)
CC complex acts by mediating ubiquitination of WNK4, an inhibitor of
CC potassium channel KCNJ1, leading to WNK4 degradation (PubMed:23387299,
CC PubMed:23453970, PubMed:23576762, PubMed:23665031). The BCR(KLHL3)
CC complex also mediates ubiquitination and degradation of CLDN8, a tight-
CC junction protein required for paracellular chloride transport in the
CC kidney (By similarity). {ECO:0000250|UniProtKB:E0CZ16,
CC ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:22406640,
CC ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970,
CC ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:14528312}.
CC -!- SUBUNIT: Homodimer (PubMed:28052936). Component of the BCR(KLHL3) E3
CC ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1
CC (Probable) (PubMed:23453970, PubMed:23576762, PubMed:23573258).
CC Interacts with SLC12A3 (PubMed:22406640). Interacts with WNK1 and WNK4
CC (PubMed:23387299, PubMed:23453970, PubMed:23573258, PubMed:23576762,
CC PubMed:23665031, PubMed:26435498, PubMed:27727489). Interacts with
CC CLDN8 (By similarity). {ECO:0000250|UniProtKB:E0CZ16,
CC ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:22406640,
CC ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970,
CC ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031,
CC ECO:0000269|PubMed:26435498, ECO:0000269|PubMed:27727489,
CC ECO:0000269|PubMed:28052936}.
CC -!- INTERACTION:
CC Q9UH77; P55212: CASP6; NbExp=3; IntAct=EBI-8524663, EBI-718729;
CC Q9UH77; Q13618: CUL3; NbExp=7; IntAct=EBI-8524663, EBI-456129;
CC Q9UH77; O75190-2: DNAJB6; NbExp=3; IntAct=EBI-8524663, EBI-12593112;
CC Q9UH77; P22607: FGFR3; NbExp=3; IntAct=EBI-8524663, EBI-348399;
CC Q9UH77; P06396: GSN; NbExp=3; IntAct=EBI-8524663, EBI-351506;
CC Q9UH77; P01112: HRAS; NbExp=3; IntAct=EBI-8524663, EBI-350145;
CC Q9UH77; Q14145: KEAP1; NbExp=3; IntAct=EBI-8524663, EBI-751001;
CC Q9UH77; O14901: KLF11; NbExp=3; IntAct=EBI-8524663, EBI-948266;
CC Q9UH77; Q53G59: KLHL12; NbExp=3; IntAct=EBI-8524663, EBI-740929;
CC Q9UH77; O95198: KLHL2; NbExp=3; IntAct=EBI-8524663, EBI-746999;
CC Q9UH77; P13473-2: LAMP2; NbExp=3; IntAct=EBI-8524663, EBI-21591415;
CC Q9UH77; O14787-2: TNPO2; NbExp=3; IntAct=EBI-8524663, EBI-12076664;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC {ECO:0000269|PubMed:22406640}. Cytoplasm, cytosol
CC {ECO:0000269|PubMed:22406640}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=A; Synonyms=KLHL3A {ECO:0000303|PubMed:10843806};
CC IsoId=Q9UH77-1; Sequence=Displayed;
CC Name=B; Synonyms=KLHL3B {ECO:0000303|PubMed:10843806};
CC IsoId=Q9UH77-2; Sequence=VSP_002816;
CC Name=C; Synonyms=KLHL3C {ECO:0000303|PubMed:10843806};
CC IsoId=Q9UH77-3; Sequence=VSP_002817;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:22406640}.
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 (PubMed:26435498, PubMed:27727489). Phosphorylation at Ser-433 is
CC increased by insulin (PubMed:26435498). {ECO:0000269|PubMed:26435498,
CC ECO:0000269|PubMed:27727489}.
CC -!- DISEASE: Pseudohypoaldosteronism 2D (PHA2D) [MIM:614495]: A disorder
CC characterized by severe hypertension, hyperkalemia, hyperchloremia,
CC hyperchloremic metabolic acidosis, and correction of physiologic
CC abnormalities by thiazide diuretics. PHA2D inheritance is autosomal
CC dominant or recessive. {ECO:0000269|PubMed:22266938,
CC ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299,
CC ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762,
CC ECO:0000269|PubMed:23665031, ECO:0000269|PubMed:26435498,
CC ECO:0000269|PubMed:27026694, ECO:0000269|PubMed:27780982,
CC ECO:0000269|PubMed:28052936, ECO:0000269|PubMed:28511177}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- CAUTION: The BCR(KLHL3) complex was initially thought to act by
CC mediating ubiquitination of SLC12A3/NCC (PubMed:22406640). However, it
CC was later shown that effects on SLC12A3/NCC are indirect and caused by
CC impaired ubiquitination of WNK4 (PubMed:23387299).
CC {ECO:0000305|PubMed:22406640, ECO:0000305|PubMed:23387299}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB97127.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=BAA86443.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF208068; AAF20938.1; -; mRNA.
DR EMBL; AF208069; AAF20939.1; -; mRNA.
DR EMBL; AF208070; AAF20995.1; -; mRNA.
DR EMBL; AB032955; BAA86443.1; ALT_INIT; mRNA.
DR EMBL; AK314707; BAG37254.1; -; mRNA.
DR EMBL; AC004021; AAB97127.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC092318; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC106775; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471062; EAW62183.1; -; Genomic_DNA.
DR CCDS; CCDS4192.1; -. [Q9UH77-1]
DR CCDS; CCDS58969.1; -. [Q9UH77-3]
DR CCDS; CCDS58970.1; -. [Q9UH77-2]
DR RefSeq; NP_001244123.1; NM_001257194.1. [Q9UH77-2]
DR RefSeq; NP_001244124.1; NM_001257195.1. [Q9UH77-3]
DR RefSeq; NP_059111.2; NM_017415.2. [Q9UH77-1]
DR PDB; 4CH9; X-ray; 1.84 A; A/B=298-587.
DR PDB; 4HXI; X-ray; 3.51 A; A=24-276.
DR PDB; 5NKP; X-ray; 2.80 A; A/B=298-587.
DR PDBsum; 4CH9; -.
DR PDBsum; 4HXI; -.
DR PDBsum; 5NKP; -.
DR AlphaFoldDB; Q9UH77; -.
DR SMR; Q9UH77; -.
DR BioGRID; 117637; 34.
DR CORUM; Q9UH77; -.
DR ELM; Q9UH77; -.
DR IntAct; Q9UH77; 14.
DR MINT; Q9UH77; -.
DR STRING; 9606.ENSP00000312397; -.
DR iPTMnet; Q9UH77; -.
DR PhosphoSitePlus; Q9UH77; -.
DR BioMuta; KLHL3; -.
DR DMDM; 13431657; -.
DR EPD; Q9UH77; -.
DR MassIVE; Q9UH77; -.
DR PaxDb; Q9UH77; -.
DR PeptideAtlas; Q9UH77; -.
DR PRIDE; Q9UH77; -.
DR ProteomicsDB; 84282; -. [Q9UH77-1]
DR ProteomicsDB; 84283; -. [Q9UH77-2]
DR ProteomicsDB; 84284; -. [Q9UH77-3]
DR Antibodypedia; 14776; 269 antibodies from 28 providers.
DR DNASU; 26249; -.
DR Ensembl; ENST00000309755.9; ENSP00000312397.4; ENSG00000146021.15. [Q9UH77-1]
DR Ensembl; ENST00000506491.5; ENSP00000424828.1; ENSG00000146021.15. [Q9UH77-3]
DR Ensembl; ENST00000508657.5; ENSP00000422099.1; ENSG00000146021.15. [Q9UH77-2]
DR GeneID; 26249; -.
DR KEGG; hsa:26249; -.
DR MANE-Select; ENST00000309755.9; ENSP00000312397.4; NM_017415.3; NP_059111.2.
DR UCSC; uc003lbr.6; human. [Q9UH77-1]
DR CTD; 26249; -.
DR DisGeNET; 26249; -.
DR GeneCards; KLHL3; -.
DR GeneReviews; KLHL3; -.
DR HGNC; HGNC:6354; KLHL3.
DR HPA; ENSG00000146021; Tissue enhanced (brain).
DR MalaCards; KLHL3; -.
DR MIM; 605775; gene.
DR MIM; 614495; phenotype.
DR neXtProt; NX_Q9UH77; -.
DR OpenTargets; ENSG00000146021; -.
DR Orphanet; 300525; Pseudohypoaldosteronism type 2D.
DR PharmGKB; PA30144; -.
DR VEuPathDB; HostDB:ENSG00000146021; -.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000157891; -.
DR HOGENOM; CLU_004253_14_2_1; -.
DR InParanoid; Q9UH77; -.
DR OMA; NHKTNEW; -.
DR OrthoDB; 635140at2759; -.
DR PhylomeDB; Q9UH77; -.
DR TreeFam; TF329218; -.
DR PathwayCommons; Q9UH77; -.
DR Reactome; R-HSA-8951664; Neddylation.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q9UH77; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 26249; 15 hits in 1108 CRISPR screens.
DR ChiTaRS; KLHL3; human.
DR GeneWiki; KLHL3; -.
DR GenomeRNAi; 26249; -.
DR Pharos; Q9UH77; Tbio.
DR PRO; PR:Q9UH77; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q9UH77; protein.
DR Bgee; ENSG00000146021; Expressed in cerebellar vermis and 178 other tissues.
DR ExpressionAtlas; Q9UH77; baseline and differential.
DR Genevisible; Q9UH77; HS.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0003779; F:actin binding; IEA:UniProtKB-KW.
DR GO; GO:0097602; F:cullin family protein binding; IPI:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; TAS:ProtInc.
DR GO; GO:0072156; P:distal tubule morphogenesis; IMP:UniProtKB.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0050801; P:ion homeostasis; IMP:UniProtKB.
DR GO; GO:0055075; P:potassium ion homeostasis; IEA:Ensembl.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:Ensembl.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0070294; P:renal sodium ion absorption; IMP:UniProtKB.
DR GO; GO:0061912; P:selective autophagy; TAS:ARUK-UCL.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA: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; 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; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Actin-binding; Alternative splicing; Cytoplasm; Cytoskeleton;
KW Disease variant; Kelch repeat; Phosphoprotein; Reference proteome; Repeat;
KW Ubl conjugation pathway.
FT CHAIN 1..587
FT /note="Kelch-like protein 3"
FT /id="PRO_0000119103"
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 MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:26435498"
FT MOD_RES 295
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:26435498"
FT MOD_RES 375
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:26435498"
FT MOD_RES 376
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:26435498"
FT MOD_RES 433
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:26435498,
FT ECO:0000269|PubMed:27727489"
FT VAR_SEQ 1..82
FT /note="Missing (in isoform C)"
FT /evidence="ECO:0000303|PubMed:10843806"
FT /id="VSP_002817"
FT VAR_SEQ 1..32
FT /note="Missing (in isoform B)"
FT /evidence="ECO:0000303|PubMed:10843806"
FT /id="VSP_002816"
FT VARIANT 77
FT /note="A -> E (in PHA2D; impaired interaction with CUL3;
FT dbSNP:rs199469623)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23665031"
FT /id="VAR_067501"
FT VARIANT 78
FT /note="M -> V (in PHA2D; impaired interaction with CUL3;
FT dbSNP:rs199469624)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067502"
FT VARIANT 85
FT /note="E -> A (in PHA2D; impaired interaction with CUL3;
FT dbSNP:rs199469625)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067503"
FT VARIANT 164
FT /note="C -> F (in PHA2D; impaired interaction with CUL3; de
FT novo mutation; dbSNP:rs199469626)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23665031"
FT /id="VAR_067504"
FT VARIANT 228
FT /note="R -> G (in PHA2D)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067505"
FT VARIANT 309
FT /note="Q -> R (in PHA2D; impaired interaction with WNK1;
FT dbSNP:rs199469627)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23665031,
FT ECO:0000269|PubMed:28511177"
FT /id="VAR_067506"
FT VARIANT 322
FT /note="F -> C (in PHA2D; dbSNP:rs199469639)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067507"
FT VARIANT 336
FT /note="R -> I (in PHA2D; dbSNP:rs199469640)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067508"
FT VARIANT 340
FT /note="A -> V (in PHA2D; does not affect interaction with
FT WNK1 or CUL3; dbSNP:rs199469628)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067509"
FT VARIANT 361
FT /note="V -> M (in PHA2D)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067510"
FT VARIANT 362
FT /note="R -> W (in PHA2D; dbSNP:rs200892557)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067511"
FT VARIANT 384
FT /note="R -> Q (in PHA2D; impaired interaction with WNK1;
FT dbSNP:rs199469629)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067512"
FT VARIANT 384
FT /note="R -> W (in PHA2D; dbSNP:rs951676369)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067513"
FT VARIANT 387
FT /note="L -> P (in PHA2D; abolished interaction with WNK1;
FT dbSNP:rs199469630)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23665031,
FT ECO:0000269|PubMed:27780982"
FT /id="VAR_067514"
FT VARIANT 398
FT /note="A -> V (in PHA2D; dbSNP:rs387907155)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067515"
FT VARIANT 410
FT /note="S -> L (in PHA2D; impaired interaction with WNK1;
FT dbSNP:rs199469641)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299"
FT /id="VAR_067516"
FT VARIANT 426
FT /note="P -> L (in PHA2D; dbSNP:rs387907156)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067517"
FT VARIANT 427
FT /note="M -> T (in PHA2D; dbSNP:rs199469642)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067518"
FT VARIANT 431
FT /note="R -> Q (in PHA2D; dbSNP:rs199469643)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067519"
FT VARIANT 432
FT /note="S -> N (in PHA2D; impaired interaction with WNK1;
FT dbSNP:rs199469631)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299"
FT /id="VAR_067520"
FT VARIANT 433
FT /note="S -> G (in PHA2D; decreased interaction with WNK4)"
FT /evidence="ECO:0000269|PubMed:22406640,
FT ECO:0000269|PubMed:26435498"
FT /id="VAR_067521"
FT VARIANT 433
FT /note="S -> N (in PHA2D; dbSNP:rs199469632)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067522"
FT VARIANT 438
FT /note="V -> I (found in a patient with hypertension;
FT unknown pathological significance; dbSNP:rs907779058)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067523"
FT VARIANT 494
FT /note="A -> T (in PHA2D; does not affect interaction with
FT WNK1 or CUL3; dbSNP:rs199469633)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067524"
FT VARIANT 498
FT /note="H -> Y (in PHA2D)"
FT /evidence="ECO:0000269|PubMed:27026694"
FT /id="VAR_079630"
FT VARIANT 500
FT /note="G -> V (in PHA2D; dbSNP:rs746774345)"
FT /evidence="ECO:0000269|PubMed:22406640"
FT /id="VAR_067525"
FT VARIANT 501
FT /note="P -> T (in PHA2D; dbSNP:rs199469634)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067526"
FT VARIANT 528
FT /note="R -> C (in PHA2D; impaired interaction with WNK1;
FT dbSNP:rs199469635)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299,
FT ECO:0000269|PubMed:23665031"
FT /id="VAR_067527"
FT VARIANT 528
FT /note="R -> H (in PHA2D; dominant negative effect due to
FT homodimer formation; impaired interaction with WNK1 and
FT WNK4 and impaired ubiquitination of WNK4;
FT dbSNP:rs199469636)"
FT /evidence="ECO:0000269|PubMed:22266938,
FT ECO:0000269|PubMed:22406640, ECO:0000269|PubMed:23387299,
FT ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762,
FT ECO:0000269|PubMed:28052936"
FT /id="VAR_067528"
FT VARIANT 529
FT /note="N -> K (in PHA2D; impaired interaction with WNK1;
FT dbSNP:rs562736621)"
FT /evidence="ECO:0000269|PubMed:22406640,
FT ECO:0000269|PubMed:23387299"
FT /id="VAR_067529"
FT VARIANT 553
FT /note="S -> L (in PHA2D; dbSNP:rs1367184898)"
FT /evidence="ECO:0000269|PubMed:28511177"
FT /id="VAR_079631"
FT VARIANT 557
FT /note="Y -> C (in PHA2D; dbSNP:rs199469645)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067530"
FT VARIANT 575
FT /note="R -> W (in PHA2D; dbSNP:rs199469646)"
FT /evidence="ECO:0000269|PubMed:22266938"
FT /id="VAR_067531"
FT MUTAGEN 433
FT /note="S->E,D: Phosphomimetic mutant that shows decreased
FT interaction with WNK4."
FT /evidence="ECO:0000269|PubMed:26435498"
FT CONFLICT 227
FT /note="T -> N (in Ref. 1; AAF20938)"
FT /evidence="ECO:0000305"
FT STRAND 301..306
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 309..314
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 317..321
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 322..325
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 326..331
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 337..339
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 341..345
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 348..355
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 357..368
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 369..372
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 373..376
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 388..392
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 395..399
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 404..407
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 411..415
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 416..419
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 420..424
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 435..439
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 442..446
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 451..454
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 460..464
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 465..468
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 469..472
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 484..488
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 491..495
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 507..510
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 512..514
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 517..520
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 531..535
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 538..542
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 545..550
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 554..558
FT /evidence="ECO:0007829|PDB:4CH9"
FT TURN 559..562
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 563..566
FT /evidence="ECO:0007829|PDB:4CH9"
FT STRAND 575..577
FT /evidence="ECO:0007829|PDB:5NKP"
FT STRAND 579..584
FT /evidence="ECO:0007829|PDB:4CH9"
SQ SEQUENCE 587 AA; 64970 MW; C5026A246620BEA1 CRC64;
MEGESVKLSS QTLIQAGDDE KNQRTITVNP AHMGKAFKVM NELRSKQLLC DVMIVAEDVE
IEAHRVVLAA CSPYFCAMFT GDMSESKAKK IEIKDVDGQT LSKLIDYIYT AEIEVTEENV
QVLLPAASLL QLMDVRQNCC DFLQSQLHPT NCLGIRAFAD VHTCTDLLQQ ANAYAEQHFP
EVMLGEEFLS LSLDQVCSLI SSDKLTVSSE EKVFEAVISW INYEKETRLE HMAKLMEHVR
LPLLPRDYLV QTVEEEALIK NNNTCKDFLI EAMKYHLLPL DQRLLIKNPR TKPRTPVSLP
KVMIVVGGQA PKAIRSVECY DFEEDRWDQI 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
