KLH24_HUMAN
ID KLH24_HUMAN Reviewed; 600 AA.
AC Q6TFL4; A5PLN8; Q9H620; Q9NXT9;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Kelch-like protein 24;
DE AltName: Full=Kainate receptor-interacting protein for GluR6;
DE Short=KRIP6;
DE AltName: Full=Protein DRE1;
GN Name=KLHL24; Synonyms=DRE1;
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] (ISOFORM 1).
RA Huang C.Q., Wu S.L., Liu S.;
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Zhang X.-M., Liu L.-D., Li Q.-H.;
RT "Function analysis on a microRNA encoded by HSV-1.";
RL Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 109-573 (ISOFORM 2).
RC TISSUE=Colon;
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] (ISOFORM 1).
RC TISSUE=Colon endothelium, and Rectum tumor;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND INVOLVEMENT IN
RP EBSSH.
RX PubMed=27889062; DOI=10.1016/j.ajhg.2016.11.005;
RA He Y., Maier K., Leppert J., Hausser I., Schwieger-Briel A., Weibel L.,
RA Theiler M., Kiritsi D., Busch H., Boerries M., Hannula-Jouppi K.,
RA Heikkilae H., Tasanen K., Castiglia D., Zambruno G., Has C.;
RT "Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause
RT Skin Fragility.";
RL Am. J. Hum. Genet. 99:1395-1404(2016).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, MUTAGENESIS OF LYS-32; TYR-90 AND ALA-175,
RP IDENTIFICATION IN THE BCR(KLHL24) COMPLEX, INTERACTION WITH CUL3 AND KRT14,
RP AUTOUBIQUITINATION, AND INVOLVEMENT IN EBSSH.
RX PubMed=27798626; DOI=10.1038/ng.3701;
RA Lin Z., Li S., Feng C., Yang S., Wang H., Ma D., Zhang J., Gou M., Bu D.,
RA Zhang T., Kong X., Wang X., Sarig O., Ren Y., Dai L., Liu H., Zhang J.,
RA Li F., Hu Y., Padalon-Brauch G., Vodo D., Zhou F., Chen T., Deng H.,
RA Sprecher E., Yang Y., Tan X.;
RT "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14
RT and human skin fragility.";
RL Nat. Genet. 48:1508-1516(2016).
CC -!- FUNCTION: Necessary to maintain the balance between intermediate
CC filament stability and degradation, a process that is essential for
CC skin integrity (PubMed:27889062). As part of the BCR(KLHL24) E3
CC ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls
CC its levels during keratinocytes differentiation (PubMed:27798626).
CC Specifically reduces kainate receptor-mediated currents in hippocampal
CC neurons, most probably by modulating channel properties (By
CC similarity). {ECO:0000250|UniProtKB:Q56A24,
CC ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}.
CC -!- SUBUNIT: Forms homodimers. Interacts with GRIK2 (By similarity).
CC Component of the BCR(KLHL24) E3 ubiquitin ligase complex, composed of
CC CUL3, RBX1 and KLHL24. Interacts with CUL3. Interacts with KRT14
CC (PubMed:27798626). {ECO:0000250|UniProtKB:Q56A24,
CC ECO:0000269|PubMed:27798626}.
CC -!- INTERACTION:
CC Q6TFL4; Q8NEY4-2: ATP6V1C2; NbExp=3; IntAct=EBI-2510117, EBI-10270867;
CC Q6TFL4; Q14145: KEAP1; NbExp=3; IntAct=EBI-2510117, EBI-751001;
CC Q6TFL4; Q53G59: KLHL12; NbExp=3; IntAct=EBI-2510117, EBI-740929;
CC Q6TFL4; O43639: NCK2; NbExp=3; IntAct=EBI-2510117, EBI-713635;
CC -!- SUBCELLULAR LOCATION: Perikaryon. Cell projection, axon
CC {ECO:0000250|UniProtKB:Q56A24}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q56A24, ECO:0000269|PubMed:27889062}. Cell
CC junction, desmosome {ECO:0000269|PubMed:27889062}. Cell junction,
CC adherens junction {ECO:0000269|PubMed:27889062}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6TFL4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6TFL4-2; Sequence=VSP_028644, VSP_028645;
CC -!- TISSUE SPECIFICITY: Expressed in the skin (PubMed:27889062,
CC PubMed:27798626). Found in keratinocytes, dermal fibroblasts, and
CC melanocytes (PubMed:27889062). Basal-layer keratinocytes have lower
CC KLHL24 expression than suprabasal keratinocytes (PubMed:27798626).
CC {ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}.
CC -!- PTM: Autoubiquitinated. Autoubiquitination leads to proteasomal
CC degradation and is necessary to control KLHL24 levels.
CC {ECO:0000269|PubMed:27798626}.
CC -!- DISEASE: Epidermolysis bullosa simplex, generalized, with scarring and
CC hair loss (EBSSH) [MIM:617294]: A form of epidermolysis bullosa, a
CC group of mechano-bullous disorders characterized by structural skin
CC fragility, recurrent blister formation and erosion of the skin and
CC mucous membranes occurring spontaneously or after mild trauma.
CC Epidermolysis bullosa simplex is characterized by intraepidermal tissue
CC separation that occurs within the basal keratinocytes at the bottom
CC layer of epidermis. EBSSH is an autosomal dominant epidermolysis
CC bullosa simplex, presenting at birth with extensive skin defects on the
CC extremities, leaving behind hypopigmentation and atrophy with a whirled
CC pattern. Cutaneous fragility and generalized blistering persist during
CC childhood and decrease in adulthood. Adult patients have
CC dyspigmentation and atrophy of the skin, scars, follicular
CC atrophoderma, sparse body hair, progressive diffuse alopecia of the
CC scalp, diffuse palmoplantar keratoderma, and nail changes.
CC {ECO:0000269|PubMed:27798626, ECO:0000269|PubMed:27889062}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Gain-of-function mutations that lead to excessive ubiquitination
CC and degradation of KRT14 result in compromised mechanical integrity of
CC basal keratinocytes. Under this pathological condition, trivial
CC mechanical stress can induce blister formation at the basal layer of
CC skin. {ECO:0000269|PubMed:27798626}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA90921.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAB15447.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AY422472; AAR13703.1; -; mRNA.
DR EMBL; DQ925701; ABI96896.1; -; mRNA.
DR EMBL; AK000066; BAA90921.1; ALT_INIT; mRNA.
DR EMBL; AK026326; BAB15447.1; ALT_SEQ; mRNA.
DR EMBL; BX648466; CAI46031.1; -; mRNA.
DR EMBL; BX648812; CAI46002.1; -; mRNA.
DR EMBL; BC142993; AAI42994.1; -; mRNA.
DR CCDS; CCDS3246.1; -. [Q6TFL4-1]
DR RefSeq; NP_060114.2; NM_017644.3. [Q6TFL4-1]
DR RefSeq; XP_005247609.1; XM_005247552.2. [Q6TFL4-1]
DR RefSeq; XP_005247610.1; XM_005247553.1.
DR RefSeq; XP_005247611.1; XM_005247554.2.
DR RefSeq; XP_005247612.1; XM_005247555.1.
DR RefSeq; XP_005247613.1; XM_005247556.1.
DR RefSeq; XP_011511240.1; XM_011512938.2.
DR RefSeq; XP_016862148.1; XM_017006659.1.
DR RefSeq; XP_016862149.1; XM_017006660.1.
DR AlphaFoldDB; Q6TFL4; -.
DR SMR; Q6TFL4; -.
DR BioGRID; 120159; 70.
DR CORUM; Q6TFL4; -.
DR IntAct; Q6TFL4; 18.
DR STRING; 9606.ENSP00000395012; -.
DR GlyGen; Q6TFL4; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q6TFL4; -.
DR PhosphoSitePlus; Q6TFL4; -.
DR BioMuta; KLHL24; -.
DR DMDM; 74722812; -.
DR EPD; Q6TFL4; -.
DR jPOST; Q6TFL4; -.
DR MassIVE; Q6TFL4; -.
DR MaxQB; Q6TFL4; -.
DR PaxDb; Q6TFL4; -.
DR PeptideAtlas; Q6TFL4; -.
DR PRIDE; Q6TFL4; -.
DR ProteomicsDB; 67392; -. [Q6TFL4-1]
DR ProteomicsDB; 67393; -. [Q6TFL4-2]
DR Antibodypedia; 54833; 87 antibodies from 14 providers.
DR DNASU; 54800; -.
DR Ensembl; ENST00000242810.11; ENSP00000242810.6; ENSG00000114796.16. [Q6TFL4-1]
DR Ensembl; ENST00000454652.6; ENSP00000395012.1; ENSG00000114796.16. [Q6TFL4-1]
DR Ensembl; ENST00000476808.1; ENSP00000419010.1; ENSG00000114796.16. [Q6TFL4-2]
DR GeneID; 54800; -.
DR KEGG; hsa:54800; -.
DR MANE-Select; ENST00000242810.11; ENSP00000242810.6; NM_017644.3; NP_060114.2.
DR UCSC; uc003flv.4; human. [Q6TFL4-1]
DR CTD; 54800; -.
DR DisGeNET; 54800; -.
DR GeneCards; KLHL24; -.
DR HGNC; HGNC:25947; KLHL24.
DR HPA; ENSG00000114796; Low tissue specificity.
DR MalaCards; KLHL24; -.
DR MIM; 611295; gene.
DR MIM; 617294; phenotype.
DR neXtProt; NX_Q6TFL4; -.
DR OpenTargets; ENSG00000114796; -.
DR Orphanet; 508529; Intermediate epidermolysis bullosa simplex with cardiomyopathy.
DR PharmGKB; PA142671576; -.
DR VEuPathDB; HostDB:ENSG00000114796; -.
DR eggNOG; KOG1721; Eukaryota.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000154345; -.
DR HOGENOM; CLU_004253_14_6_1; -.
DR InParanoid; Q6TFL4; -.
DR OMA; QTFNKQE; -.
DR OrthoDB; 279729at2759; -.
DR PhylomeDB; Q6TFL4; -.
DR TreeFam; TF351654; -.
DR PathwayCommons; Q6TFL4; -.
DR SignaLink; Q6TFL4; -.
DR BioGRID-ORCS; 54800; 7 hits in 1114 CRISPR screens.
DR ChiTaRS; KLHL24; human.
DR GenomeRNAi; 54800; -.
DR Pharos; Q6TFL4; Tbio.
DR PRO; PR:Q6TFL4; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q6TFL4; protein.
DR Bgee; ENSG00000114796; Expressed in endothelial cell and 220 other tissues.
DR ExpressionAtlas; Q6TFL4; baseline and differential.
DR Genevisible; Q6TFL4; HS.
DR GO; GO:0005912; C:adherens junction; IDA:UniProtKB.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IMP:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0030057; C:desmosome; IDA:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0045109; P:intermediate filament organization; IMP:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:2000312; P:regulation of kainate selective glutamate receptor activity; IEA:InterPro.
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; IPR030596; KLHL24.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR PANTHER; PTHR24412:SF215; PTHR24412:SF215; 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; SSF117281; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell junction; Cell projection; Cytoplasm;
KW Epidermolysis bullosa; Kelch repeat; Reference proteome; Repeat;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..600
FT /note="Kelch-like protein 24"
FT /id="PRO_0000261594"
FT DOMAIN 66..133
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 168..270
FT /note="BACK"
FT REPEAT 314..363
FT /note="Kelch 1"
FT REPEAT 365..407
FT /note="Kelch 2"
FT REPEAT 408..454
FT /note="Kelch 3"
FT REPEAT 456..502
FT /note="Kelch 4"
FT REPEAT 504..544
FT /note="Kelch 5"
FT REPEAT 546..592
FT /note="Kelch 6"
FT VAR_SEQ 535..537
FT /note="ENC -> VIT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_028644"
FT VAR_SEQ 538..600
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_028645"
FT MUTAGEN 32
FT /note="K->R: Increased protein stability."
FT /evidence="ECO:0000269|PubMed:27798626"
FT MUTAGEN 90
FT /note="Y->A: Weak interaction with CUL3. Weak
FT autoubiquitination."
FT /evidence="ECO:0000269|PubMed:27798626"
FT MUTAGEN 175
FT /note="A->V: Weak interaction with CUL3. Weak
FT autoubiquitination."
FT /evidence="ECO:0000269|PubMed:27798626"
FT CONFLICT 489
FT /note="P -> R (in Ref. 3; BAA90921)"
FT /evidence="ECO:0000305"
FT CONFLICT 515
FT /note="Y -> C (in Ref. 3; BAB15447)"
FT /evidence="ECO:0000305"
FT CONFLICT 536
FT /note="N -> D (in Ref. 5; AAI42994)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 600 AA; 68361 MW; 54538E2BF447A56B CRC64;
MVLILGRRLN REDLGVRDSP ATKRKVFEMD PKSLTGHEFF DFSSGSSHAE NILQIFNEFR
DSRLFTDVII CVEGKEFPCH RAVLSACSSY FRAMFCNDHR ESREMLVEIN GILAEAMECF
LQYVYTGKVK ITTENVQYLF ETSSLFQISV LRDACAKFLE EQLDPCNCLG IQRFADTHSL
KTLFTKCKNF ALQTFEDVSQ HEEFLELDKD ELIDYICSDE LVIGKEEMVF EAVMRWVYRA
VDLRRPLLHE LLTHVRLPLL HPNYFVQTVE VDQLIQNSPE CYQLLHEARR YHILGNEMMS
PRTRPRRSTG YSEVIVVVGG CERVGGFNLP YTECYDPVTG EWKSLAKLPE FTKSEYAVCA
LRNDILVSGG RINSRDVWIY NSQLNIWIRV ASLNKGRWRH KMAVLLGKVY VVGGYDGQNR
LSSVECYDSF SNRWTEVAPL KEAVSSPAVT SCVGKLFVIG GGPDDNTCSD KVQSYDPETN
SWLLRAAIPI AKRCITAVSL NNLIYVAGGL TKAIYCYDPV EDYWMHVQNT FSRQENCGMS
VCNGKIYILG GRRENGEATD TILCYDPATS IITGVAAMPR PVSYHGCVTI HRYNEKCFKL
