LRAD4_HUMAN
ID LRAD4_HUMAN Reviewed; 306 AA.
AC O15165; B3KNT9; E9PAY9; K7EN38; O15166; O15167; O15168; Q5U646; Q6NXP3;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Low-density lipoprotein receptor class A domain-containing protein 4;
GN Name=LDLRAD4; Synonyms=C18orf1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA-1; ALPHA-2; BETA-1 AND BETA-2).
RC TISSUE=Brain;
RX PubMed=9479497; DOI=10.1006/geno.1997.5118;
RA Yoshikawa T., Sanders A.R., Esterling L.E., Detera-Wadleigh S.D.;
RT "Multiple transcriptional variants and RNA editing in C18orf1, a novel gene
RT with LDLRA and transmembrane domains on 18p11.2.";
RL Genomics 47:246-257(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6).
RC TISSUE=Brain;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D.,
RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J.,
RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L.,
RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A.,
RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C.,
RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS ALPHA-2; 5 AND 8).
RC TISSUE=Brain;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 6-251 (ISOFORM 7).
RC TISSUE=Testis;
RA Ebert L., Heil O., Hennig S., Neubert P., Partsch E., Peters M.,
RA Radelof U., Schneider D., Korn B.;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=19461657; DOI=10.1038/jhg.2009.47;
RA Meerabux J.M., Ohba H., Iwayama Y., Maekawa M., Detera-Wadleigh S.D.,
RA DeLisi L.E., Yoshikawa T.;
RT "Analysis of a t(18;21)(p11.1;p11.1) translocation in a family with
RT schizophrenia.";
RL J. Hum. Genet. 54:386-391(2009).
RN [8]
RP FUNCTION, INTERACTION WITH PMEPA1; SMAD2 AND SMAD3, SUBCELLULAR LOCATION,
RP AND MOTIF.
RX PubMed=24627487; DOI=10.1074/jbc.m114.558981;
RA Nakano N., Maeyama K., Sakata N., Itoh F., Akatsu R., Nakata M., Katsu Y.,
RA Ikeno S., Togawa Y., Vo Nguyen T.T., Watanabe Y., Kato M., Itoh S.;
RT "C18 ORF1, a novel negative regulator of transforming growth factor-beta
RT signaling.";
RL J. Biol. Chem. 289:12680-12692(2014).
CC -!- FUNCTION: Functions as a negative regulator of TGF-beta signaling and
CC thereby probably plays a role in cell proliferation, differentiation,
CC apoptosis, motility, extracellular matrix production and
CC immunosuppression. In the canonical TGF-beta pathway, ZFYVE9/SARA
CC recruits the intracellular signal transducer and transcriptional
CC modulators SMAD2 and SMAD3 to the TGF-beta receptor. Phosphorylated by
CC the receptor, SMAD2 and SMAD3 then form a heteromeric complex with
CC SMAD4 that translocates to the nucleus to regulate transcription.
CC Through interaction with SMAD2 and SMAD3, LDLRAD4 may compete with
CC ZFYVE9 and SMAD4 and prevent propagation of the intracellular signal.
CC {ECO:0000269|PubMed:24627487}.
CC -!- SUBUNIT: Interacts with PMEPA1. Interacts (via the SMAD interaction
CC motif) with SMAD2 and SMAD3. {ECO:0000269|PubMed:24627487}.
CC -!- INTERACTION:
CC O15165-2; O43681: GET3; NbExp=3; IntAct=EBI-13302279, EBI-2515857;
CC O15165-2; O43765: SGTA; NbExp=3; IntAct=EBI-13302279, EBI-347996;
CC O15165-2; Q8N966: ZDHHC22; NbExp=3; IntAct=EBI-13302279, EBI-10268111;
CC -!- SUBCELLULAR LOCATION: Early endosome membrane
CC {ECO:0000269|PubMed:24627487}; Single-pass membrane protein
CC {ECO:0000269|PubMed:24627487}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=Alpha-1;
CC IsoId=O15165-1; Sequence=Displayed;
CC Name=Alpha-2;
CC IsoId=O15165-2; Sequence=VSP_006440;
CC Name=Beta-1;
CC IsoId=O15165-3; Sequence=VSP_006439;
CC Name=Beta-2;
CC IsoId=O15165-4; Sequence=VSP_006439, VSP_006440;
CC Name=5;
CC IsoId=O15165-5; Sequence=VSP_013901;
CC Name=6;
CC IsoId=O15165-6; Sequence=VSP_043253;
CC Name=7;
CC IsoId=O15165-7; Sequence=VSP_043253, VSP_006440;
CC Name=8;
CC IsoId=O15165-8; Sequence=VSP_054772;
CC -!- TISSUE SPECIFICITY: Expressed in lymphocytes.
CC {ECO:0000269|PubMed:19461657}.
CC -!- DOMAIN: The SMAD interaction motif is required for interaction with
CC SMAD2 and SMAD3 and the negative regulation of TGF-beta signaling.
CC {ECO:0000269|PubMed:24627487}.
CC -!- SIMILARITY: Belongs to the PMEPA1 family. {ECO:0000305}.
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DR EMBL; AF009424; AAC52023.1; -; mRNA.
DR EMBL; AF009425; AAC52024.1; -; mRNA.
DR EMBL; AF009426; AAC52025.1; -; mRNA.
DR EMBL; AF009427; AAC52026.1; -; mRNA.
DR EMBL; AK055028; BAG51451.1; -; mRNA.
DR EMBL; AP001010; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002439; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002505; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP005131; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471113; EAX01514.1; -; Genomic_DNA.
DR EMBL; BC029958; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC030199; AAH30199.1; -; mRNA.
DR EMBL; BC066971; AAH66971.1; -; mRNA.
DR EMBL; BX114947; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS32793.1; -. [O15165-1]
DR CCDS; CCDS32794.1; -. [O15165-2]
DR CCDS; CCDS32795.1; -. [O15165-6]
DR CCDS; CCDS42415.1; -. [O15165-7]
DR CCDS; CCDS62392.1; -. [O15165-5]
DR CCDS; CCDS62393.1; -. [O15165-8]
DR RefSeq; NP_001003674.1; NM_001003674.3. [O15165-6]
DR RefSeq; NP_001003675.1; NM_001003675.3. [O15165-7]
DR RefSeq; NP_001263178.1; NM_001276249.1. [O15165-5]
DR RefSeq; NP_001263180.1; NM_001276251.1. [O15165-8]
DR RefSeq; NP_852146.1; NM_181481.4. [O15165-1]
DR RefSeq; NP_852147.1; NM_181482.4. [O15165-2]
DR RefSeq; XP_005258197.1; XM_005258140.1.
DR RefSeq; XP_006722416.1; XM_006722353.1. [O15165-1]
DR RefSeq; XP_006722417.1; XM_006722354.1. [O15165-1]
DR RefSeq; XP_011524040.1; XM_011525738.1. [O15165-5]
DR RefSeq; XP_016881454.1; XM_017025965.1. [O15165-5]
DR RefSeq; XP_016881455.1; XM_017025966.1. [O15165-5]
DR RefSeq; XP_016881456.1; XM_017025967.1. [O15165-5]
DR RefSeq; XP_016881457.1; XM_017025968.1. [O15165-5]
DR RefSeq; XP_016881458.1; XM_017025969.1. [O15165-5]
DR RefSeq; XP_016881459.1; XM_017025970.1. [O15165-5]
DR RefSeq; XP_016881460.1; XM_017025971.1. [O15165-5]
DR AlphaFoldDB; O15165; -.
DR BioGRID; 107209; 58.
DR IntAct; O15165; 41.
DR STRING; 9606.ENSP00000352420; -.
DR iPTMnet; O15165; -.
DR PhosphoSitePlus; O15165; -.
DR SwissPalm; O15165; -.
DR BioMuta; LDLRAD4; -.
DR MassIVE; O15165; -.
DR PaxDb; O15165; -.
DR PeptideAtlas; O15165; -.
DR PRIDE; O15165; -.
DR ProteomicsDB; 19107; -.
DR ProteomicsDB; 48486; -. [O15165-1]
DR ProteomicsDB; 48487; -. [O15165-2]
DR ProteomicsDB; 48488; -. [O15165-3]
DR ProteomicsDB; 48489; -. [O15165-4]
DR ProteomicsDB; 48490; -. [O15165-5]
DR ProteomicsDB; 48491; -. [O15165-6]
DR Antibodypedia; 21959; 71 antibodies from 10 providers.
DR DNASU; 753; -.
DR Ensembl; ENST00000359446.10; ENSP00000352420.5; ENSG00000168675.19. [O15165-1]
DR Ensembl; ENST00000399848.7; ENSP00000382741.2; ENSG00000168675.19. [O15165-2]
DR Ensembl; ENST00000585931.5; ENSP00000466772.1; ENSG00000168675.19. [O15165-5]
DR Ensembl; ENST00000586765.1; ENSP00000474783.1; ENSG00000168675.19. [O15165-7]
DR Ensembl; ENST00000587757.5; ENSP00000466178.1; ENSG00000168675.19. [O15165-6]
DR Ensembl; ENST00000677744.1; ENSP00000504022.1; ENSG00000168675.19. [O15165-5]
DR Ensembl; ENST00000677910.1; ENSP00000503996.1; ENSG00000168675.19. [O15165-5]
DR Ensembl; ENST00000679091.1; ENSP00000503185.1; ENSG00000168675.19. [O15165-1]
DR GeneID; 753; -.
DR KEGG; hsa:753; -.
DR MANE-Select; ENST00000359446.11; ENSP00000352420.5; NM_001378100.1; NP_001365029.1.
DR UCSC; uc002ksb.4; human. [O15165-1]
DR CTD; 753; -.
DR DisGeNET; 753; -.
DR GeneCards; LDLRAD4; -.
DR HGNC; HGNC:1224; LDLRAD4.
DR HPA; ENSG00000168675; Tissue enhanced (brain, lymphoid tissue).
DR MIM; 606571; gene.
DR neXtProt; NX_O15165; -.
DR OpenTargets; ENSG00000168675; -.
DR PharmGKB; PA25593; -.
DR VEuPathDB; HostDB:ENSG00000168675; -.
DR eggNOG; ENOG502QRYK; Eukaryota.
DR GeneTree; ENSGT00390000000724; -.
DR HOGENOM; CLU_074371_0_1_1; -.
DR InParanoid; O15165; -.
DR OMA; GASEIMC; -.
DR OrthoDB; 1189277at2759; -.
DR PhylomeDB; O15165; -.
DR TreeFam; TF331681; -.
DR PathwayCommons; O15165; -.
DR SignaLink; O15165; -.
DR BioGRID-ORCS; 753; 12 hits in 1067 CRISPR screens.
DR ChiTaRS; LDLRAD4; human.
DR GenomeRNAi; 753; -.
DR Pharos; O15165; Tbio.
DR PRO; PR:O15165; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; O15165; protein.
DR Bgee; ENSG00000168675; Expressed in endothelial cell and 189 other tissues.
DR ExpressionAtlas; O15165; baseline and differential.
DR Genevisible; O15165; HS.
DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0070412; F:R-SMAD binding; IPI:UniProtKB.
DR GO; GO:0030336; P:negative regulation of cell migration; IMP:UniProtKB.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IMP:UniProtKB.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; IDA:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR CDD; cd00112; LDLa; 1.
DR Gene3D; 4.10.400.10; -; 1.
DR InterPro; IPR036055; LDL_receptor-like_sf.
DR InterPro; IPR023415; LDLR_class-A_CS.
DR InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR InterPro; IPR043445; TMEPAI/LRAD4.
DR PANTHER; PTHR16514; PTHR16514; 1.
DR Pfam; PF00057; Ldl_recept_a; 1.
DR SMART; SM00192; LDLa; 1.
DR SUPFAM; SSF57424; SSF57424; 1.
DR PROSITE; PS01209; LDLRA_1; 1.
DR PROSITE; PS50068; LDLRA_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Disulfide bond; Endosome; Membrane;
KW Reference proteome; Signal transduction inhibitor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..306
FT /note="Low-density lipoprotein receptor class A domain-
FT containing protein 4"
FT /id="PRO_0000185444"
FT TOPO_DOM 1..64
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 65..85
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 86..306
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 16..48
FT /note="LDL-receptor class A"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT REGION 286..306
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 180..183
FT /note="PPxY motif 1"
FT MOTIF 208..211
FT /note="SMAD interaction motif (SIM)"
FT MOTIF 252..255
FT /note="PPxY motif 2"
FT DISULFID 19..38
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT DISULFID 32..47
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT VAR_SEQ 1..111
FT /note="MPEAGFQATNAFTECKFTCTSGKCLYLGSLVCNQQNDCGDNSDEENCLLVTE
FT HPPPGIFNSELEFAQIIIIVVVVTVMVVVIVCLLNHYKVSTRSFINRPNQSRRREDGLP
FT -> MRLDSHLECISST (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054772"
FT VAR_SEQ 1..77
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013901"
FT VAR_SEQ 1..61
FT /note="MPEAGFQATNAFTECKFTCTSGKCLYLGSLVCNQQNDCGDNSDEENCLLVTE
FT HPPPGIFNS -> MSSDHLNNSTLKEAQFKDLFLKKA (in isoform 6 and
FT isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.6"
FT /id="VSP_043253"
FT VAR_SEQ 1..61
FT /note="MPEAGFQATNAFTECKFTCTSGKCLYLGSLVCNQQNDCGDNSDEENCLLVTE
FT HPPPGIFNS -> MAA (in isoform Beta-1 and isoform Beta-2)"
FT /evidence="ECO:0000303|PubMed:9479497"
FT /id="VSP_006439"
FT VAR_SEQ 113..130
FT /note="Missing (in isoform Alpha-2, isoform Beta-2 and
FT isoform 7)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9479497, ECO:0000303|Ref.6"
FT /id="VSP_006440"
FT CONFLICT 125
FT /note="R -> Q (in Ref. 5; AAH66971)"
FT /evidence="ECO:0000305"
FT CONFLICT 135
FT /note="P -> T (in Ref. 5; AAH66971)"
FT /evidence="ECO:0000305"
FT CONFLICT 194
FT /note="P -> T (in Ref. 5; AAH66971)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 306 AA; 33900 MW; F48EF66E329201BD CRC64;
MPEAGFQATN AFTECKFTCT SGKCLYLGSL VCNQQNDCGD NSDEENCLLV TEHPPPGIFN
SELEFAQIII IVVVVTVMVV VIVCLLNHYK VSTRSFINRP NQSRRREDGL PQEGCLWPSD
SAAPRLGASE IMHAPRSRDR FTAPSFIQRD RFSRFQPTYP YVQHEIDLPP TISLSDGEEP
PPYQGPCTLQ LRDPEQQMEL NRESVRAPPN RTIFDSDLID IAMYSGGPCP PSSNSGISAS
TCSSNGRMEG PPPTYSEVMG HHPGASFLHH QRSNAHRGSR LQFQQNNAES TIVPIKGKDR
KPGNLV
