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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
 
 
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