KLH15_HUMAN
ID KLH15_HUMAN Reviewed; 604 AA.
AC Q96M94; Q32MN3; Q8NDA3; Q96BM6; Q9C0I6;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 21-FEB-2006, sequence version 2.
DT 03-AUG-2022, entry version 157.
DE RecName: Full=Kelch-like protein 15;
GN Name=KLHL15; Synonyms=KIAA1677;
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 MRNA].
RC TISSUE=Testis;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Duodenum;
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 [3]
RP PROTEIN SEQUENCE OF 2-22; 47-75; 139-151; 214-235; 250-271; 277-297;
RP 356-450; 460-471; 533-542; 572-577 AND 582-602, FUNCTION, INTERACTION WITH
RP CUL3 AND RBBP8, SUBCELLULAR LOCATION, CLEAVAGE OF INITIATOR METHIONINE,
RP MASS SPECTROMETRY, AND MUTAGENESIS OF ASN-132 AND ILE-136.
RX PubMed=27561354; DOI=10.1038/ncomms12628;
RA Ferretti L.P., Himmels S.F., Trenner A., Walker C., von Aesch C.,
RA Eggenschwiler A., Murina O., Enchev R.I., Peter M., Freire R., Porro A.,
RA Sartori A.A.;
RT "Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-
RT tune DNA-end resection.";
RL Nat. Commun. 7:12628-12628(2016).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 84-604.
RC TISSUE=Brain;
RX PubMed=11214970; DOI=10.1093/dnares/7.6.347;
RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIX. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:347-355(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 421-604.
RC TISSUE=Testis;
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 [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 AND PPP2R5B, HOMODIMERIZATION, AND
RP MUTAGENESIS OF ASP-32; HIS-45; 72-ILE--LYS-75; ARG-318; 335-GLU--LEU-337
RP AND GLU-371.
RX PubMed=23135275; DOI=10.1074/jbc.m112.420281;
RA Oberg E.A., Nifoussi S.K., Gingras A.C., Strack S.;
RT "Selective proteasomal degradation of the B'beta subunit of protein
RT phosphatase 2A by the E3 ubiquitin ligase adaptor Kelch-like 15.";
RL J. Biol. Chem. 287:43378-43389(2012).
RN [8]
RP INVOLVEMENT IN XLID103.
RX PubMed=24817631; DOI=10.1002/ajmg.a.36602;
RA Mignon-Ravix C., Cacciagli P., Choucair N., Popovici C., Missirian C.,
RA Milh M., Megarbane A., Busa T., Julia S., Girard N., Badens C., Sigaudy S.,
RA Philip N., Villard L.;
RT "Intragenic rearrangements in X-linked intellectual deficiency: results of
RT a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as
RT potential XLID genes.";
RL Am. J. Med. Genet. A 164A:1991-1997(2014).
RN [9]
RP INVOLVEMENT IN XLID103.
RX PubMed=25644381; DOI=10.1038/mp.2014.193;
RA Hu H., Haas S.A., Chelly J., Van Esch H., Raynaud M., de Brouwer A.P.,
RA Weinert S., Froyen G., Frints S.G., Laumonnier F., Zemojtel T., Love M.I.,
RA Richard H., Emde A.K., Bienek M., Jensen C., Hambrock M., Fischer U.,
RA Langnick C., Feldkamp M., Wissink-Lindhout W., Lebrun N., Castelnau L.,
RA Rucci J., Montjean R., Dorseuil O., Billuart P., Stuhlmann T., Shaw M.,
RA Corbett M.A., Gardner A., Willis-Owen S., Tan C., Friend K.L., Belet S.,
RA van Roozendaal K.E., Jimenez-Pocquet M., Moizard M.P., Ronce N., Sun R.,
RA O'Keeffe S., Chenna R., van Boemmel A., Goeke J., Hackett A., Field M.,
RA Christie L., Boyle J., Haan E., Nelson J., Turner G., Baynam G.,
RA Gillessen-Kaesbach G., Mueller U., Steinberger D., Budny B.,
RA Badura-Stronka M., Latos-Bielenska A., Ousager L.B., Wieacker P.,
RA Rodriguez Criado G., Bondeson M.L., Anneren G., Dufke A., Cohen M.,
RA Van Maldergem L., Vincent-Delorme C., Echenne B., Simon-Bouy B.,
RA Kleefstra T., Willemsen M., Fryns J.P., Devriendt K., Ullmann R.,
RA Vingron M., Wrogemann K., Wienker T.F., Tzschach A., van Bokhoven H.,
RA Gecz J., Jentsch T.J., Chen W., Ropers H.H., Kalscheuer V.M.;
RT "X-exome sequencing of 405 unresolved families identifies seven novel
RT intellectual disability genes.";
RL Mol. Psychiatry 21:133-148(2016).
CC -!- FUNCTION: Substrate-specific adapter for CUL3 E3 ubiquitin-protein
CC ligase complex (PubMed:14528312). Acts as an adapter for CUL3 to target
CC the serine/threonine-protein phosphatase 2A (PP2A) subunit PPP2R5B for
CC ubiquitination and subsequent proteasomal degradation, thus promoting
CC exchange with other regulatory subunits (PubMed:23135275). Acts as an
CC adapter for CUL3 to target the DNA-end resection factor RBBP8/CtIP for
CC ubiquitination and subsequent proteasomal degradation. Through the
CC regulation of RBBP8/CtIP protein turnover, plays a key role in DNA
CC damage response, favoring DNA double-strand repair through error-prone
CC non-homologous end joining (NHEJ) over error-free, RBBP8-mediated
CC homologous recombination (HR) (PubMed:27561354).
CC {ECO:0000269|PubMed:14528312, ECO:0000269|PubMed:23135275,
CC ECO:0000269|PubMed:27561354}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Homodimer. Dimerization does not affect PPP2R5B-binding, but
CC is required for its proteasomal degradation (PubMed:23135275).
CC Interacts with CUL3 (PubMed:27561354, PubMed:14528312,
CC PubMed:23135275). Directly interacts with PPP2R5B; this interaction
CC leads to PPP2R5B proteasomal degradation (PubMed:23135275). Interacts
CC with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal
CC degradation (PubMed:27561354). {ECO:0000269|PubMed:14528312,
CC ECO:0000269|PubMed:23135275, ECO:0000269|PubMed:27561354}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:27561354}.
CC -!- DISEASE: Intellectual developmental disorder, X-linked 103 (XLID103)
CC [MIM:300982]: A form of intellectual disability, a disorder
CC characterized by significantly below average general intellectual
CC functioning associated with impairments in adaptive behavior and
CC manifested during the developmental period. Intellectual deficiency is
CC the only primary symptom of non-syndromic X-linked forms, while
CC syndromic forms present with associated physical, neurological and/or
CC psychiatric manifestations. {ECO:0000269|PubMed:24817631,
CC ECO:0000269|PubMed:25644381}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
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DR EMBL; AK057298; BAB71415.1; -; mRNA.
DR EMBL; BC015415; AAH15415.1; -; mRNA.
DR EMBL; BC109058; AAI09059.1; -; mRNA.
DR EMBL; BC109059; AAI09060.1; -; mRNA.
DR EMBL; AB051464; BAB21768.1; -; mRNA.
DR EMBL; AL834313; CAD38983.1; -; mRNA.
DR CCDS; CCDS35217.1; -.
DR RefSeq; NP_085127.2; NM_030624.2.
DR RefSeq; XP_006724581.1; XM_006724518.1.
DR AlphaFoldDB; Q96M94; -.
DR SMR; Q96M94; -.
DR BioGRID; 123224; 89.
DR IntAct; Q96M94; 40.
DR MINT; Q96M94; -.
DR STRING; 9606.ENSP00000332791; -.
DR iPTMnet; Q96M94; -.
DR PhosphoSitePlus; Q96M94; -.
DR BioMuta; KLHL15; -.
DR DMDM; 88909167; -.
DR EPD; Q96M94; -.
DR jPOST; Q96M94; -.
DR MassIVE; Q96M94; -.
DR PaxDb; Q96M94; -.
DR PeptideAtlas; Q96M94; -.
DR PRIDE; Q96M94; -.
DR ProteomicsDB; 77318; -.
DR Antibodypedia; 24558; 94 antibodies from 26 providers.
DR DNASU; 80311; -.
DR Ensembl; ENST00000328046.8; ENSP00000332791.8; ENSG00000174010.10.
DR Ensembl; ENST00000684871.1; ENSP00000509774.1; ENSG00000174010.10.
DR Ensembl; ENST00000685367.1; ENSP00000509439.1; ENSG00000174010.10.
DR Ensembl; ENST00000689334.1; ENSP00000508713.1; ENSG00000174010.10.
DR Ensembl; ENST00000693269.1; ENSP00000509509.1; ENSG00000174010.10.
DR GeneID; 80311; -.
DR KEGG; hsa:80311; -.
DR MANE-Select; ENST00000328046.8; ENSP00000332791.8; NM_030624.3; NP_085127.2.
DR CTD; 80311; -.
DR DisGeNET; 80311; -.
DR GeneCards; KLHL15; -.
DR HGNC; HGNC:29347; KLHL15.
DR HPA; ENSG00000174010; Tissue enhanced (bone).
DR MalaCards; KLHL15; -.
DR MIM; 300980; gene.
DR MIM; 300982; phenotype.
DR neXtProt; NX_Q96M94; -.
DR OpenTargets; ENSG00000174010; -.
DR PharmGKB; PA134934728; -.
DR VEuPathDB; HostDB:ENSG00000174010; -.
DR eggNOG; KOG4441; Eukaryota.
DR GeneTree; ENSGT00940000159116; -.
DR HOGENOM; CLU_004253_16_1_1; -.
DR InParanoid; Q96M94; -.
DR OMA; PRHNSWL; -.
DR OrthoDB; 250404at2759; -.
DR PhylomeDB; Q96M94; -.
DR TreeFam; TF328485; -.
DR PathwayCommons; Q96M94; -.
DR SignaLink; Q96M94; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 80311; 8 hits in 746 CRISPR screens.
DR ChiTaRS; KLHL15; human.
DR GenomeRNAi; 80311; -.
DR Pharos; Q96M94; Tbio.
DR PRO; PR:Q96M94; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q96M94; protein.
DR Bgee; ENSG00000174010; Expressed in adrenal tissue and 173 other tissues.
DR ExpressionAtlas; Q96M94; baseline and differential.
DR Genevisible; Q96M94; HS.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IEA:InterPro.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:2000042; P:negative regulation of double-strand break repair via homologous recombination; IDA:UniProtKB.
DR GO; GO:0071630; P:nuclear protein quality control by the ubiquitin-proteasome system; IDA:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
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; IPR030597; KLHL15.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR PANTHER; PTHR45632:SF12; PTHR45632:SF12; 1.
DR Pfam; PF07707; BACK; 1.
DR Pfam; PF00651; BTB; 1.
DR Pfam; PF01344; Kelch_1; 3.
DR PIRSF; PIRSF037037; Kelch-like_protein_gigaxonin; 1.
DR SMART; SM00875; BACK; 1.
DR SMART; SM00225; BTB; 1.
DR SMART; SM00612; Kelch; 5.
DR SUPFAM; SSF117281; SSF117281; 1.
DR SUPFAM; SSF54695; SSF54695; 1.
DR PROSITE; PS50097; BTB; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Intellectual disability; Kelch repeat; Nucleus;
KW Reference proteome; Repeat; Ubl conjugation pathway.
FT CHAIN 1..604
FT /note="Kelch-like protein 15"
FT /id="PRO_0000223949"
FT DOMAIN 31..98
FT /note="BTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 133..237
FT /note="BACK"
FT REPEAT 328..379
FT /note="Kelch 1"
FT REPEAT 381..426
FT /note="Kelch 2"
FT REPEAT 428..473
FT /note="Kelch 3"
FT REPEAT 489..542
FT /note="Kelch 4"
FT REPEAT 544..590
FT /note="Kelch 5"
FT MUTAGEN 32
FT /note="D->A: Impaired homodimerization and PPP2R5B
FT proteasomal degradation. No effect on PPP2R5B-binding."
FT /evidence="ECO:0000269|PubMed:23135275"
FT MUTAGEN 45
FT /note="H->L: No effect on homodimerization, PPP2R5B-
FT binding, nor on PPP2R5B proteasomal degradation."
FT /evidence="ECO:0000269|PubMed:23135275"
FT MUTAGEN 72..75
FT /note="IHLK->AHAA: No effect on PPP2R5B-binding, nor on
FT homodimerization, but loss of CUL3 recruitment to the
FT KLHL15/PPP2R5B complex and impaired PPP2R5B proteasomal
FT degradation."
FT /evidence="ECO:0000269|PubMed:23135275"
FT MUTAGEN 132
FT /note="N->A: Decreased interaction with CUL3, especially
FT with the neddylated form of CUL3."
FT /evidence="ECO:0000269|PubMed:27561354"
FT MUTAGEN 136
FT /note="I->A: Decreased interaction with CUL3, especially
FT with the neddylated form of CUL3."
FT /evidence="ECO:0000269|PubMed:27561354"
FT MUTAGEN 318
FT /note="R->E: Impaired PPP2R5B-binding and proteasomal
FT degradation."
FT /evidence="ECO:0000269|PubMed:23135275"
FT MUTAGEN 335..337
FT /note="EEL->REA: Impaired PPP2R5B-binding and proteasomal
FT degradation."
FT /evidence="ECO:0000269|PubMed:23135275"
FT MUTAGEN 371
FT /note="E->R: Impaired PPP2R5B-binding and proteasomal
FT degradation."
FT /evidence="ECO:0000269|PubMed:23135275"
FT MUTAGEN 386
FT /note="G->C: Decreased interaction with RBBP8 and complete
FT loss of nuclear localization, found exclusively in the
FT cytoplasm."
FT /evidence="ECO:0000269|PubMed:27561354"
FT MUTAGEN 552
FT /note="Y->A: Decreased interaction with RBBP8 and increased
FT DNA-end resection and homologous recombination frequency
FT following DNA double-strand breaks compared to the wild-
FT type protein. No significant change in subcellular
FT location."
FT /evidence="ECO:0000269|PubMed:27561354"
FT CONFLICT 297
FT /note="K -> E (in Ref. 1; BAB71415)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 604 AA; 69775 MW; E37606E8AE367C83 CRC64;
MAGDVEGFCS SIHDTSVSAG FRALYEEGLL LDVTLVIEDH QFQAHKALLA TQSDYFRIMF
TADMRERDQD KIHLKGLTAT GFSHVLQFMY YGTIELSMNT VHEILQAAMY VQLIEVVKFC
CSFLLAKICL ENCAEIMRLL DDFGVNIEGV REKLDTFLLD NFVPLMSRPD FLSYLSFEKL
MSYLDNDHLS RFPEIELYEA VQSWLRHDRR RWRHTDTIIQ NIRFCLMTPT SVFEKVKTSE
FYRYSRQLRY EVDQALNYFQ NVHQQPLLDM KSSRIRSAKP QTTVFRGMIG HSMVNSKILL
LKKPRVWWEL EGPQVPLRPD CLAIVNNFVF LLGGEELGPD GEFHASSKVF RYDPRQNSWL
QMADMSVPRS EFAVGVIGKF IYAVAGRTRD ETFYSTERYD ITNDKWEFVD PYPVNKYGHE
GTVLNNKLFI TGGITSSSTS KQVCVFDPSK EGTIEQRTRR TQVVTNCWEN KSKMNYARCF
HKMISYNGKL YVFGGVCVIL RASFESQGCP STEVYNPETD QWTILASMPI GRSGHGVTVL
DKQIMVLGGL CYNGHYSDSI LTFDPDENKW KEDEYPRMPC KLDGLQVCNL HFPDYVLDEV
RRCN
