LZTR1_HUMAN
ID LZTR1_HUMAN Reviewed; 840 AA.
AC Q8N653; Q14776; Q20WK0;
DT 11-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 11-APR-2003, sequence version 2.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Leucine-zipper-like transcriptional regulator 1 {ECO:0000303|PubMed:7633402};
DE Short=LZTR-1 {ECO:0000303|PubMed:7633402};
GN Name=LZTR1 {ECO:0000303|PubMed:7633402, ECO:0000312|HGNC:HGNC:6742};
GN Synonyms=TCFL2;
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].
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Duodenal adenocarcinoma;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-840, AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=7633402; DOI=10.1093/hmg/4.4.541;
RA Kurahashi H., Akagi K., Inazawa J., Ohta T., Niikawa N., Kayatani F.,
RA Sano T., Okada S., Nishisho I.;
RT "Isolation and characterization of a novel gene deleted in DiGeorge
RT syndrome.";
RL Hum. Mol. Genet. 4:541-549(1995).
RN [5]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION, AND DEGRADATION.
RX PubMed=16356934; DOI=10.1074/jbc.m509073200;
RA Nacak T.G., Leptien K., Fellner D., Augustin H.G., Kroll J.;
RT "The BTB-kelch protein LZTR-1 is a novel Golgi protein that is degraded
RT upon induction of apoptosis.";
RL J. Biol. Chem. 281:5065-5071(2006).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [7]
RP INVOLVEMENT IN SWNTS2, AND VARIANTS SWNTS2 LEU-122; ARG-404; GLY-456;
RP GLN-466; LEU-520; CYS-688 AND ILE-813.
RX PubMed=24362817; DOI=10.1038/ng.2855;
RA Piotrowski A., Xie J., Liu Y.F., Poplawski A.B., Gomes A.R., Madanecki P.,
RA Fu C., Crowley M.R., Crossman D.K., Armstrong L., Babovic-Vuksanovic D.,
RA Bergner A., Blakeley J.O., Blumenthal A.L., Daniels M.S., Feit H.,
RA Gardner K., Hurst S., Kobelka C., Lee C., Nagy R., Rauen K.A., Slopis J.M.,
RA Suwannarat P., Westman J.A., Zanko A., Korf B.R., Messiaen L.M.;
RT "Germline loss-of-function mutations in LZTR1 predispose to an inherited
RT disorder of multiple schwannomas.";
RL Nat. Genet. 46:182-187(2014).
RN [8]
RP INVOLVEMENT IN NS10, VARIANTS NS10 CYS-119; ASN-247; ARG-248; CYS-284 AND
RP TYR-287, AND VARIANTS LEU-447 AND VAL-647.
RX PubMed=25795793; DOI=10.1136/jmedgenet-2015-103018;
RA Yamamoto G.L., Aguena M., Gos M., Hung C., Pilch J., Fahiminiya S.,
RA Abramowicz A., Cristian I., Buscarilli M., Naslavsky M.S., Malaquias A.C.,
RA Zatz M., Bodamer O., Majewski J., Jorge A.A., Pereira A.C., Kim C.A.,
RA Passos-Bueno M.R., Bertola D.R.;
RT "Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.";
RL J. Med. Genet. 52:413-421(2015).
RN [9]
RP FUNCTION, SUBUNIT, PATHWAY, INTERACTION WITH CUL3; KRAS, NRAS AND HRAS,
RP SUBCELLULAR LOCATION, VARIANT SWNTS2 PRO-812, CHARACTERIZATION OF VARIANTS
RP SWNTS2 LEU-122; ARG-187; ARG-202; ARG-404; GLN-466; CYS-688 AND PRO-812,
RP AND CHARACTERIZATION OF VARIANT NS10 726-TYR--ILE-840 DEL.
RX PubMed=30442762; DOI=10.1126/science.aap7607;
RA Steklov M., Pandolfi S., Baietti M.F., Batiuk A., Carai P., Najm P.,
RA Zhang M., Jang H., Renzi F., Cai Y., Abbasi Asbagh L., Pastor T.,
RA De Troyer M., Simicek M., Radaelli E., Brems H., Legius E., Tavernier J.,
RA Gevaert K., Impens F., Messiaen L., Nussinov R., Heymans S., Eyckerman S.,
RA Sablina A.A.;
RT "Mutations in LZTR1 drive human disease by dysregulating RAS
RT ubiquitination.";
RL Science 362:1177-1182(2018).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CUL3, VARIANTS GLM
RP ARG-105; GLY-198; ARG-248; ILE-288 AND TRP-810, CHARACTERIZATION OF
RP VARIANTS GLM ARG-105; GLY-198; ARG-248; ILE-288 AND TRP-810,
RP CHARACTERIZATION OF VARIANTS NS10 CYS-119; ASN-247; ARG-248 AND TYR-287,
RP AND CHARACTERIZATION OF VARIANTS SWNTS2 LEU-122; ARG-404; GLY-456; GLN-466;
RP LEU-520; CYS-688 AND ILE-813.
RX PubMed=30442766; DOI=10.1126/science.aap8210;
RA Bigenzahn J.W., Collu G.M., Kartnig F., Pieraks M., Vladimer G.I.,
RA Heinz L.X., Sedlyarov V., Schischlik F., Fauster A., Rebsamen M.,
RA Parapatics K., Blomen V.A., Mueller A.C., Winter G.E., Kralovics R.,
RA Brummelkamp T.R., Mlodzik M., Superti-Furga G.;
RT "LZTR1 is a regulator of RAS ubiquitination and signaling.";
RL Science 362:1171-1177(2018).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS NS2 ASP-121;
RP ALA-217; GLN-563 AND THR-821, CHARACTERIZATION OF VARIANTS NS10 ASN-247;
RP ARG-248 AND CYS-284, CHARACTERIZATION OF VARIANTS SWNTS2 GLN-170; ARG-286
RP AND ARG-400, AND MUTAGENESIS OF MET-91 AND TYR-193.
RX PubMed=30481304; DOI=10.1093/hmg/ddy412;
RA Motta M., Fidan M., Bellacchio E., Pantaleoni F., Schneider-Heieck K.,
RA Coppola S., Borck G., Salviati L., Zenker M., Cirstea I.C., Tartaglia M.;
RT "Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the
RT kelch domain substrate-recognition surface and enhance RAS-MAPK
RT signaling.";
RL Hum. Mol. Genet. 28:1007-1022(2019).
RN [12]
RP VARIANTS SWNTS2 GLN-170; ARG-202; ARG-286; 322-GLU--ILE-840 DEL; VAL-392;
RP ARG-528; CYS-539; GLY-654; TYR-668; CYS-688 AND 762-GLN--ILE-840 DEL.
RX PubMed=25480913; DOI=10.1212/wnl.0000000000001129;
RA Smith M.J., Isidor B., Beetz C., Williams S.G., Bhaskar S.S., Richer W.,
RA O'Sullivan J., Anderson B., Daly S.B., Urquhart J.E., Fryer A.,
RA Rustad C.F., Mills S.J., Samii A., du Plessis D., Halliday D., Barbarot S.,
RA Bourdeaut F., Newman W.G., Evans D.G.;
RT "Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis.";
RL Neurology 84:141-147(2015).
RN [13]
RP VARIANTS SWNTS2 ARG-71; 81-TYR--ILE-840 DEL; VAL-125 DEL; ARG-187;
RP 210-ARG--ILE-840 DEL; CYS-284; 340-ARG--ILE-840 DEL; ARG-400; GLU-465;
RP 603-VAL--ILE-840 DEL; TRP-697; ARG-760 AND 762-GLN--ILE-840 DEL.
RX PubMed=25335493; DOI=10.1038/ejhg.2014.220;
RA Paganini I., Chang V.Y., Capone G.L., Vitte J., Benelli M., Barbetti L.,
RA Sestini R., Trevisson E., Hulsebos T.J., Giovannini M., Nelson S.F.,
RA Papi L.;
RT "Expanding the mutational spectrum of LZTR1 in schwannomatosis.";
RL Eur. J. Hum. Genet. 23:963-968(2015).
RN [14]
RP VARIANTS NS2 ASP-121; TRP-170; THR-205; 210-ARG--ILE-840 DEL; ALA-217;
RP GLN-563; GLY-688; GLN-697; 726-TYR--ILE-840 DEL; GLN-755 AND THR-821, AND
RP INVOLVEMENT IN NS2.
RX PubMed=29469822; DOI=10.1038/gim.2017.249;
RG Members of the Undiagnosed Diseases Network;
RA Johnston J.J., van der Smagt J.J., Rosenfeld J.A., Pagnamenta A.T.,
RA Alswaid A., Baker E.H., Blair E., Borck G., Brinkmann J., Craigen W.,
RA Dung V.C., Emrick L., Everman D.B., van Gassen K.L., Gulsuner S.,
RA Harr M.H., Jain M., Kuechler A., Leppig K.A., McDonald-McGinn D.M.,
RA Can N.T.B., Peleg A., Roeder E.R., Rogers R.C., Sagi-Dain L., Sapp J.C.,
RA Schaeffer A.A., Schanze D., Stewart H., Taylor J.C., Verbeek N.E.,
RA Walkiewicz M.A., Zackai E.H., Zweier C., Zenker M., Lee B., Biesecker L.G.;
RT "Autosomal recessive Noonan syndrome associated with biallelic LZTR1
RT variants.";
RL Genet. Med. 20:1175-1185(2018).
RN [15]
RP VARIANT NS10 LEU-294.
RX PubMed=29959388; DOI=10.1038/s41436-018-0041-5;
RA Nakaguma M., Jorge A.A.L., Arnhold I.J.P.;
RT "Noonan syndrome associated with growth hormone deficiency with biallelic
RT LZTR1 variants.";
RL Genet. Med. 21:260-260(2019).
RN [16]
RP VARIANTS NS10 SER-143; ARG-248; ASN-253 DEL; GLN-283 AND PRO-554, VARIANT
RP NS2 HIS-701, AND INTERACTION WITH RAF1; SHOC2 AND PPP1CB.
RX PubMed=30368668; DOI=10.1007/s00439-018-1951-7;
RA Umeki I., Niihori T., Abe T., Kanno S.I., Okamoto N., Mizuno S.,
RA Kurosawa K., Nagasaki K., Yoshida M., Ohashi H., Inoue S.I., Matsubara Y.,
RA Fujiwara I., Kure S., Aoki Y.;
RT "Delineation of LZTR1 mutation-positive patients with Noonan syndrome and
RT identification of LZTR1 binding to RAF1-PPP1CB complexes.";
RL Hum. Genet. 138:21-35(2019).
CC -!- FUNCTION: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3
CC ubiquitin-protein ligase complex that mediates ubiquitination of Ras
CC (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS) (PubMed:30442762,
CC PubMed:30442766, PubMed:30481304). Is a negative regulator of RAS-MAPK
CC signaling that acts by controlling Ras levels and decreasing Ras
CC association with membranes (PubMed:30442762, PubMed:30442766,
CC PubMed:30481304). {ECO:0000269|PubMed:30442762,
CC ECO:0000269|PubMed:30442766, ECO:0000269|PubMed:30481304}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:30442762}.
CC -!- SUBUNIT: Homodimer (PubMed:30442762). Component of the BCR(LZTR1) E3
CC ubiquitin ligase complex, at least composed of CUL3, LZTR1 and RBX1
CC (PubMed:30442762, PubMed:30442766). Interacts with Ras (K-Ras/KRAS, N-
CC Ras/NRAS and H-Ras/HRAS) (PubMed:30442762). Interacts with RAF1
CC (PubMed:30368668). Interacts with SHOC2 (PubMed:30368668). Interacts
CC with PPP1CB (PubMed:30368668). {ECO:0000269|PubMed:30368668,
CC ECO:0000269|PubMed:30442762, ECO:0000269|PubMed:30442766}.
CC -!- INTERACTION:
CC Q8N653; P60520: GABARAPL2; NbExp=3; IntAct=EBI-2350056, EBI-720116;
CC Q8N653; Q9UGJ1: TUBGCP4; NbExp=4; IntAct=EBI-2350056, EBI-1052544;
CC -!- SUBCELLULAR LOCATION: Endomembrane system {ECO:0000269|PubMed:30442762,
CC ECO:0000269|PubMed:30442766}. Recycling endosome
CC {ECO:0000269|PubMed:30442762}. Golgi apparatus
CC {ECO:0000269|PubMed:16356934, ECO:0000269|PubMed:30481304}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal brain, heart, kidney, liver and
CC lung. {ECO:0000269|PubMed:7633402}.
CC -!- PTM: Phosphorylated on tyrosine upon induction of apoptosis, leading to
CC its degradation by the proteasome. {ECO:0000269|PubMed:16356934}.
CC -!- DISEASE: Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant
CC central nervous system neoplasms derived from glial cells. They
CC comprise astrocytomas and glioblastoma multiforme that are derived from
CC astrocytes, oligodendrogliomas derived from oligodendrocytes and
CC ependymomas derived from ependymocytes. {ECO:0000269|PubMed:30442766}.
CC Note=The protein represented in this entry may be involved in disease
CC pathogenesis.
CC -!- DISEASE: Schwannomatosis 2 (SWNTS2) [MIM:615670]: A cancer
CC predisposition syndrome in which patients develop multiple non-
CC vestibular schwannomas, benign neoplasms that arise from Schwann cells
CC of the cranial, peripheral, and autonomic nerves.
CC {ECO:0000269|PubMed:24362817, ECO:0000269|PubMed:25335493,
CC ECO:0000269|PubMed:25480913, ECO:0000269|PubMed:30442762,
CC ECO:0000269|PubMed:30442766, ECO:0000269|PubMed:30481304}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- DISEASE: Noonan syndrome 10 (NS10) [MIM:616564]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial dysmorphic
CC features such as hypertelorism, a downward eyeslant and low-set
CC posteriorly rotated ears, and a high incidence of congenital heart
CC defects and hypertrophic cardiomyopathy. Other features can include a
CC short neck with webbing or redundancy of skin, deafness, motor delay,
CC variable intellectual deficits, multiple skeletal defects,
CC cryptorchidism, and bleeding diathesis. Individuals with Noonan
CC syndrome are at risk of juvenile myelomonocytic leukemia, a
CC myeloproliferative disorder characterized by excessive production of
CC myelomonocytic cells. NS10 inheritance is autosomal dominant.
CC {ECO:0000269|PubMed:25795793, ECO:0000269|PubMed:29959388,
CC ECO:0000269|PubMed:30368668, ECO:0000269|PubMed:30442762,
CC ECO:0000269|PubMed:30442766, ECO:0000269|PubMed:30481304}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Noonan syndrome 2 (NS2) [MIM:605275]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial dysmorphic
CC features such as hypertelorism, a downward eyeslant and low-set
CC posteriorly rotated ears, and a high incidence of congenital heart
CC defects and hypertrophic cardiomyopathy. Other features can include a
CC short neck with webbing or redundancy of skin, deafness, motor delay,
CC variable intellectual deficits, multiple skeletal defects,
CC cryptorchidism, and bleeding diathesis. Individuals with Noonan
CC syndrome are at risk of juvenile myelomonocytic leukemia, a
CC myeloproliferative disorder characterized by excessive production of
CC myelomonocytic cells. NS2 inheritance is autosomal recessive.
CC {ECO:0000269|PubMed:29469822, ECO:0000269|PubMed:30368668,
CC ECO:0000269|PubMed:30481304}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the LZTR1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA07508.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; CT841521; CAJ86451.1; -; mRNA.
DR EMBL; CH471176; EAX02923.1; -; Genomic_DNA.
DR EMBL; BC026214; AAH26214.2; -; mRNA.
DR EMBL; D38496; BAA07508.1; ALT_FRAME; mRNA.
DR CCDS; CCDS33606.1; -.
DR PIR; I54388; I54388.
DR RefSeq; NP_006758.2; NM_006767.3.
DR AlphaFoldDB; Q8N653; -.
DR SMR; Q8N653; -.
DR BioGRID; 113852; 110.
DR IntAct; Q8N653; 65.
DR MINT; Q8N653; -.
DR STRING; 9606.ENSP00000215739; -.
DR iPTMnet; Q8N653; -.
DR PhosphoSitePlus; Q8N653; -.
DR BioMuta; LZTR1; -.
DR DMDM; 29839558; -.
DR EPD; Q8N653; -.
DR jPOST; Q8N653; -.
DR MassIVE; Q8N653; -.
DR MaxQB; Q8N653; -.
DR PaxDb; Q8N653; -.
DR PeptideAtlas; Q8N653; -.
DR PRIDE; Q8N653; -.
DR ProteomicsDB; 72130; -.
DR Antibodypedia; 8368; 138 antibodies from 27 providers.
DR DNASU; 8216; -.
DR Ensembl; ENST00000646124.2; ENSP00000496779.1; ENSG00000099949.21.
DR GeneID; 8216; -.
DR KEGG; hsa:8216; -.
DR MANE-Select; ENST00000646124.2; ENSP00000496779.1; NM_006767.4; NP_006758.2.
DR UCSC; uc002zto.4; human.
DR CTD; 8216; -.
DR DisGeNET; 8216; -.
DR GeneCards; LZTR1; -.
DR GeneReviews; LZTR1; -.
DR HGNC; HGNC:6742; LZTR1.
DR HPA; ENSG00000099949; Low tissue specificity.
DR MalaCards; LZTR1; -.
DR MIM; 137800; phenotype.
DR MIM; 600574; gene.
DR MIM; 605275; phenotype.
DR MIM; 615670; phenotype.
DR MIM; 616564; phenotype.
DR neXtProt; NX_Q8N653; -.
DR OpenTargets; ENSG00000099949; -.
DR Orphanet; 251579; Giant cell glioblastoma.
DR Orphanet; 251576; Gliosarcoma.
DR Orphanet; 648; Noonan syndrome.
DR Orphanet; 93921; Schwannomatosis.
DR PharmGKB; PA30506; -.
DR VEuPathDB; HostDB:ENSG00000099949; -.
DR eggNOG; KOG4693; Eukaryota.
DR GeneTree; ENSGT00940000158190; -.
DR HOGENOM; CLU_012081_0_0_1; -.
DR InParanoid; Q8N653; -.
DR OMA; ILEDHVI; -.
DR OrthoDB; 1263405at2759; -.
DR PhylomeDB; Q8N653; -.
DR TreeFam; TF314081; -.
DR PathwayCommons; Q8N653; -.
DR SignaLink; Q8N653; -.
DR SIGNOR; Q8N653; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 8216; 36 hits in 1123 CRISPR screens.
DR ChiTaRS; LZTR1; human.
DR GeneWiki; LZTR1; -.
DR GenomeRNAi; 8216; -.
DR Pharos; Q8N653; Tbio.
DR PRO; PR:Q8N653; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; Q8N653; protein.
DR Bgee; ENSG00000099949; Expressed in sural nerve and 93 other tissues.
DR ExpressionAtlas; Q8N653; baseline and differential.
DR Genevisible; Q8N653; HS.
DR GO; GO:0031463; C:Cul3-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; IDA:UniProtKB.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IDA:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR Gene3D; 2.120.10.80; -; 3.
DR Gene3D; 3.30.710.10; -; 2.
DR InterPro; IPR000210; BTB/POZ_dom.
DR InterPro; IPR015915; Kelch-typ_b-propeller.
DR InterPro; IPR006652; Kelch_1.
DR InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR Pfam; PF00651; BTB; 2.
DR Pfam; PF01344; Kelch_1; 2.
DR SMART; SM00225; BTB; 2.
DR SMART; SM00612; Kelch; 4.
DR SUPFAM; SSF117281; SSF117281; 2.
DR SUPFAM; SSF54695; SSF54695; 2.
DR PROSITE; PS50097; BTB; 2.
PE 1: Evidence at protein level;
KW Acetylation; Disease variant; Endosome; Golgi apparatus; Kelch repeat;
KW Membrane; Phosphoprotein; Reference proteome; Repeat;
KW Ubl conjugation pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22814378"
FT CHAIN 2..840
FT /note="Leucine-zipper-like transcriptional regulator 1"
FT /id="PRO_0000119135"
FT REPEAT 79..128
FT /note="Kelch 1"
FT /evidence="ECO:0000255"
FT REPEAT 130..185
FT /note="Kelch 2"
FT /evidence="ECO:0000255"
FT REPEAT 187..238
FT /note="Kelch 3"
FT /evidence="ECO:0000255"
FT REPEAT 239..285
FT /note="Kelch 4"
FT /evidence="ECO:0000255"
FT REPEAT 295..341
FT /note="Kelch 5"
FT /evidence="ECO:0000255"
FT REPEAT 399..450
FT /note="Kelch 6"
FT /evidence="ECO:0000255"
FT DOMAIN 443..537
FT /note="BTB 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT DOMAIN 667..736
FT /note="BTB 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00037"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT VARIANT 71
FT /note="H -> R (in SWNTS2; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081292"
FT VARIANT 81..840
FT /note="Missing (in SWNTS2)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081293"
FT VARIANT 105
FT /note="W -> R (in GLM; increased Ras signaling)"
FT /evidence="ECO:0000269|PubMed:30442766"
FT /id="VAR_081294"
FT VARIANT 119
FT /note="Y -> C (in NS10; increased Ras signaling)"
FT /evidence="ECO:0000269|PubMed:25795793,
FT ECO:0000269|PubMed:30442766"
FT /id="VAR_075657"
FT VARIANT 121
FT /note="H -> D (in NS2; unknown pathological significance;
FT no effect on RAS-MAPK signaling; no effect on stability;
FT dbSNP:rs1569154492)"
FT /evidence="ECO:0000269|PubMed:29469822,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081295"
FT VARIANT 122
FT /note="S -> L (in SWNTS2; increased Ras signaling;
FT decreased binding to Ras; dbSNP:rs587777177)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:30442762, ECO:0000269|PubMed:30442766"
FT /id="VAR_071145"
FT VARIANT 125
FT /note="Missing (in SWNTS2; unknown pathological
FT significance; dbSNP:rs755783378)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081296"
FT VARIANT 143
FT /note="N -> S (in NS10; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:30368668"
FT /id="VAR_081297"
FT VARIANT 170
FT /note="R -> Q (in SWNTS2; increased RAS-MAPK signaling;
FT dbSNP:rs781431741)"
FT /evidence="ECO:0000269|PubMed:25480913,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081298"
FT VARIANT 170
FT /note="R -> W (in NS2; when associated with T-205;
FT dbSNP:rs757502214)"
FT /evidence="ECO:0000269|PubMed:29469822"
FT /id="VAR_081299"
FT VARIANT 187
FT /note="L -> R (in SWNTS2; decreased binding to Ras)"
FT /evidence="ECO:0000269|PubMed:25335493,
FT ECO:0000269|PubMed:30442762"
FT /id="VAR_081300"
FT VARIANT 198
FT /note="R -> G (in GLM; increased Ras signaling; decreased
FT ubiquitination of Ras)"
FT /evidence="ECO:0000269|PubMed:30442766"
FT /id="VAR_081301"
FT VARIANT 202
FT /note="M -> R (in SWNTS2; decreased binding to Ras)"
FT /evidence="ECO:0000269|PubMed:25480913,
FT ECO:0000269|PubMed:30442762"
FT /id="VAR_081302"
FT VARIANT 205
FT /note="I -> T (in NS2; unknown pathological significance;
FT when associated with W-170; dbSNP:rs1287917092)"
FT /evidence="ECO:0000269|PubMed:29469822"
FT /id="VAR_081303"
FT VARIANT 210..840
FT /note="Missing (in NS2 and SWNTS2)"
FT /evidence="ECO:0000269|PubMed:25335493,
FT ECO:0000269|PubMed:29469822"
FT /id="VAR_081304"
FT VARIANT 217
FT /note="E -> A (in NS2; unknown pathological significance;
FT no effect on RAS-MAPK signaling; decreased stability)"
FT /evidence="ECO:0000269|PubMed:29469822,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081305"
FT VARIANT 247
FT /note="S -> N (in NS10; increased RAS-MAPK signaling;
FT decreased stability; no effect on localization to Golgi
FT apparatus; dbSNP:rs797045166)"
FT /evidence="ECO:0000269|PubMed:25795793,
FT ECO:0000269|PubMed:30442766, ECO:0000269|PubMed:30481304"
FT /id="VAR_075658"
FT VARIANT 248
FT /note="G -> R (in NS10 and GLM; increased RAS-MAPK
FT signaling; decreased ubiquitination of Ras; decreased
FT stability; no effect on localization to Golgi apparatus;
FT dbSNP:rs869320686)"
FT /evidence="ECO:0000269|PubMed:25795793,
FT ECO:0000269|PubMed:30368668, ECO:0000269|PubMed:30442766,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_075659"
FT VARIANT 253
FT /note="Missing (in NS10; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30368668"
FT /id="VAR_081306"
FT VARIANT 283
FT /note="R -> Q (in NS10; dbSNP:rs1223430276)"
FT /evidence="ECO:0000269|PubMed:30368668"
FT /id="VAR_081307"
FT VARIANT 284
FT /note="R -> C (in NS10 and SWNTS2; increased RAS-MAPK
FT signaling; decreased stability; no effect on localization
FT to Golgi apparatus; dbSNP:rs797045165)"
FT /evidence="ECO:0000269|PubMed:25335493,
FT ECO:0000269|PubMed:25795793, ECO:0000269|PubMed:30481304"
FT /id="VAR_075660"
FT VARIANT 286
FT /note="G -> R (in SWNTS2; unknown pathological
FT significance; no effect on stability; dbSNP:rs773016962)"
FT /evidence="ECO:0000269|PubMed:25480913,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081308"
FT VARIANT 287
FT /note="H -> Y (in NS10; increased Ras signaling)"
FT /evidence="ECO:0000269|PubMed:25795793,
FT ECO:0000269|PubMed:30442766"
FT /id="VAR_075661"
FT VARIANT 288
FT /note="T -> I (in GLM; increased Ras signaling)"
FT /evidence="ECO:0000269|PubMed:30442766"
FT /id="VAR_081309"
FT VARIANT 294
FT /note="R -> L (in NS10; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:29959388"
FT /id="VAR_081310"
FT VARIANT 322..840
FT /note="Missing (in SWNTS2)"
FT /evidence="ECO:0000269|PubMed:25480913"
FT /id="VAR_081311"
FT VARIANT 340..840
FT /note="Missing (in SWNTS2)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081312"
FT VARIANT 392
FT /note="A -> V (in SWNTS2; unknown pathological
FT significance; dbSNP:rs767354230)"
FT /evidence="ECO:0000269|PubMed:25480913"
FT /id="VAR_081313"
FT VARIANT 400
FT /note="M -> R (in SWNTS2; unknown pathological
FT significance; no effect on stability; no effect on
FT localization to Golgi apparatus)"
FT /evidence="ECO:0000269|PubMed:25335493,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081314"
FT VARIANT 404
FT /note="G -> R (in SWNTS2; increased Ras signaling;
FT decreased binding to Ras; dbSNP:rs1470449160)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:30442762, ECO:0000269|PubMed:30442766"
FT /id="VAR_071146"
FT VARIANT 447
FT /note="F -> L (in dbSNP:rs201016956)"
FT /evidence="ECO:0000269|PubMed:25795793"
FT /id="VAR_075662"
FT VARIANT 456
FT /note="V -> G (in SWNTS2; increased Ras signaling; impaired
FT subcellular location)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:30442766"
FT /id="VAR_071147"
FT VARIANT 465
FT /note="A -> E (in SWNTS2; unknown pathological
FT significance; dbSNP:rs753757778)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081315"
FT VARIANT 466
FT /note="R -> Q (in SWNTS2; increased Ras signaling;
FT decreased interaction with CUL3; impaired subcellular
FT location; impaired subcellular location;
FT dbSNP:rs587777180)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:30442762, ECO:0000269|PubMed:30442766"
FT /id="VAR_071148"
FT VARIANT 520
FT /note="P -> L (in SWNTS2; increased Ras signaling; impaired
FT subcellular location; dbSNP:rs1569157089)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:30442766"
FT /id="VAR_071149"
FT VARIANT 528
FT /note="L -> R (in SWNTS2; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25480913"
FT /id="VAR_081316"
FT VARIANT 539
FT /note="G -> C (in SWNTS2; unknown pathological
FT significance; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:25480913"
FT /id="VAR_081317"
FT VARIANT 554
FT /note="A -> P (in NS10; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:30368668"
FT /id="VAR_081318"
FT VARIANT 563
FT /note="E -> Q (in NS2; unknown pathological significance;
FT no effect on RAS-MAPK signaling; strongly decreased
FT stability; dbSNP:rs1374240053)"
FT /evidence="ECO:0000269|PubMed:29469822,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081319"
FT VARIANT 603..840
FT /note="Missing (in SWNTS2)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081320"
FT VARIANT 647
FT /note="I -> V (in dbSNP:rs148916790)"
FT /evidence="ECO:0000269|PubMed:25795793"
FT /id="VAR_075663"
FT VARIANT 654
FT /note="D -> G (in SWNTS2; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25480913"
FT /id="VAR_081321"
FT VARIANT 668
FT /note="D -> Y (in SWNTS2; unknown pathological
FT significance; dbSNP:rs776005012)"
FT /evidence="ECO:0000269|PubMed:25480913"
FT /id="VAR_081322"
FT VARIANT 688
FT /note="R -> C (in SWNTS2; increased Ras signaling;
FT decreased interaction with CUL3; impaired subcellular
FT location; dbSNP:rs587777178)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:25480913, ECO:0000269|PubMed:30442762,
FT ECO:0000269|PubMed:30442766"
FT /id="VAR_071150"
FT VARIANT 688
FT /note="R -> G (in NS2; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:29469822"
FT /id="VAR_081323"
FT VARIANT 697
FT /note="R -> Q (in NS2; dbSNP:rs370638947)"
FT /evidence="ECO:0000269|PubMed:29469822"
FT /id="VAR_081324"
FT VARIANT 697
FT /note="R -> W (in SWNTS2; unknown pathological
FT significance; dbSNP:rs751516987)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081325"
FT VARIANT 701
FT /note="P -> H (in NS2; dbSNP:rs1327579827)"
FT /evidence="ECO:0000269|PubMed:30368668"
FT /id="VAR_081326"
FT VARIANT 726..840
FT /note="Missing (in NS2; decreased ubiquitination of Ras)"
FT /evidence="ECO:0000269|PubMed:29469822,
FT ECO:0000269|PubMed:30442762"
FT /id="VAR_081327"
FT VARIANT 755
FT /note="R -> Q (in NS2; unknown pathological significance;
FT dbSNP:rs762834512)"
FT /evidence="ECO:0000269|PubMed:29469822"
FT /id="VAR_081328"
FT VARIANT 760
FT /note="C -> R (in SWNTS2; unknown pathological
FT significance; dbSNP:rs1419388177)"
FT /evidence="ECO:0000269|PubMed:25335493"
FT /id="VAR_081329"
FT VARIANT 762..840
FT /note="Missing (in SWNTS2)"
FT /evidence="ECO:0000269|PubMed:25335493,
FT ECO:0000269|PubMed:25480913"
FT /id="VAR_081330"
FT VARIANT 810
FT /note="R -> W (in GLM; increased Ras signaling;
FT dbSNP:rs776893978)"
FT /evidence="ECO:0000269|PubMed:30442766"
FT /id="VAR_081331"
FT VARIANT 812
FT /note="L -> P (in SWNTS2; decreased interaction with CUL3;
FT impaired subcellular location; decreased ubiquitination of
FT Ras; dbSNP:rs773059569)"
FT /evidence="ECO:0000269|PubMed:30442762"
FT /id="VAR_081332"
FT VARIANT 813
FT /note="S -> I (in SWNTS2; increased Ras signaling)"
FT /evidence="ECO:0000269|PubMed:24362817,
FT ECO:0000269|PubMed:30442766"
FT /id="VAR_071151"
FT VARIANT 821
FT /note="I -> T (in NS2; unknown pathological significance;
FT no effect on RAS-MAPK signaling; decreased localization to
FT Golgi apparatus; no effect on stability;
FT dbSNP:rs1275511136)"
FT /evidence="ECO:0000269|PubMed:29469822,
FT ECO:0000269|PubMed:30481304"
FT /id="VAR_081333"
FT MUTAGEN 91
FT /note="M->V: Increased RAS-MAPK signaling."
FT /evidence="ECO:0000269|PubMed:30481304"
FT MUTAGEN 193
FT /note="Y->H: Increased RAS-MAPK signaling."
FT /evidence="ECO:0000269|PubMed:30481304"
FT MUTAGEN 193
FT /note="Y->N: Increased RAS-MAPK signaling."
FT /evidence="ECO:0000269|PubMed:30481304"
FT CONFLICT 498
FT /note="G -> S (in Ref. 4; BAA07508)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 840 AA; 94719 MW; AAF172940BAEA92B CRC64;
MAGPGSTGGQ IGAAALAGGA RSKVAPSVDF DHSCSDSVEY LTLNFGPFET VHRWRRLPPC
DEFVGARRSK HTVVAYKDAI YVFGGDNGKT MLNDLLRFDV KDCSWCRAFT TGTPPAPRYH
HSAVVYGSSM FVFGGYTGDI YSNSNLKNKN DLFEYKFATG QWTEWKIEGR LPVARSAHGA
TVYSDKLWIF AGYDGNARLN DMWTIGLQDR ELTCWEEVAQ SGEIPPSCCN FPVAVCRDKM
FVFSGQSGAK ITNNLFQFEF KDKTWTRIPT EHLLRGSPPP PQRRYGHTMV AFDRHLYVFG
GAADNTLPNE LHCYDVDFQT WEVVQPSSDS EVGGAEVPER ACASEEVPTL TYEERVGFKK
SRDVFGLDFG TTSAKQPTQP ASELPSGRLF HAAAVISDAM YIFGGTVDNN IRSGEMYRFQ
FSCYPKCTLH EDYGRLWESR QFCDVEFVLG EKEECVQGHV AIVTARSRWL RRKITQARER
LAQKLEQEAA PVPREAPGVA AGGARPPLLH VAIREAEARP FEVLMQFLYT DKIKYPRKGH
VEDVLLIMDV YKLALSFQLC RLEQLCRQYI EASVDLQNVL VVCESAARLQ LSQLKEHCLN
FVVKESHFNQ VIMMKEFERL SSPLIVEIVR RKQQPPPRTP LDQPVDIGTS LIQDMKAYLE
GAGAEFCDIT LLLDGHPRPA HKAILAARSS YFEAMFRSFM PEDGQVNISI GEMVPSRQAF
ESMLRYIYYG EVNMPPEDSL YLFAAPYYYG FYNNRLQAYC KQNLEMNVTV QNVLQILEAA
DKTQALDMKR HCLHIIVHQF TKVSKLPTLR SLSQQLLLDI IDSLASHISD KQCAELGADI