NCLN_HUMAN
ID NCLN_HUMAN Reviewed; 563 AA.
AC Q969V3; D6W613; O75252; Q6FI60; Q6ZMB7; Q8TAT7; Q96H48; Q96IS7; Q9BQH9;
AC Q9BTX4; Q9NPP2;
DT 21-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2004, sequence version 2.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Nicalin;
DE AltName: Full=Nicastrin-like protein;
DE Flags: Precursor;
GN Name=NCLN;
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] (ISOFORM 1).
RC TISSUE=Carcinoma;
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 GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, Kidney, and Ovary;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 6-563 (ISOFORM 1), AND VARIANT
RP ARG-551.
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 12-563 (ISOFORM 1), AND VARIANT
RP ARG-551.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 502-563.
RG The European IMAGE consortium;
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH NOMO.
RX PubMed=15257293; DOI=10.1038/sj.emboj.7600307;
RA Haffner C., Frauli M., Topp S., Irmler M., Hofmann K., Regula J.T.,
RA Bally-Cuif L., Haass C.;
RT "Nicalin and its binding partner Nomo are novel Nodal signaling
RT antagonists.";
RL EMBO J. 23:3041-3050(2004).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NOMO AND TMEM147.
RX PubMed=20538592; DOI=10.1074/jbc.m110.132548;
RA Dettmer U., Kuhn P.H., Abou-Ajram C., Lichtenthaler S.F., Kruger M.,
RA Kremmer E., Haass C., Haffner C.;
RT "Transmembrane protein 147 (TMEM147) is a novel component of the Nicalin-
RT NOMO protein complex.";
RL J. Biol. Chem. 285:26174-26181(2010).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [12]
RP FUNCTION, AND INTERACTION WITH TMCO1; CCDC47; NOMO; TMEM147; SEC61A1;
RP SEC61B AND SEC61G.
RX PubMed=32820719; DOI=10.7554/elife.56889;
RA McGilvray P.T., Anghel S.A., Sundaram A., Zhong F., Trnka M.J.,
RA Fuller J.R., Hu H., Burlingame A.L., Keenan R.J.;
RT "An ER translocon for multi-pass membrane protein biogenesis.";
RL Elife 9:0-0(2020).
CC -!- FUNCTION: Component of a ribosome-associated translocon complex
CC involved in multi-pass membrane protein transport into the endoplasmic
CC reticulum (ER) membrane and biogenesis (PubMed:32820719). May
CC antagonize Nodal signaling and subsequent organization of axial
CC structures during mesodermal patterning, via its interaction with NOMO
CC (By similarity). {ECO:0000250|UniProtKB:Q6NZ07,
CC ECO:0000269|PubMed:32820719}.
CC -!- SUBUNIT: Forms a complex with NOMO and TMEM147, resulting in a
CC stabilization of the 3 proteins, which are otherwise quickly degraded
CC by the proteasome (PubMed:20538592). The ribosome-associated ER
CC translocon complex includes SEC61A1, SEC61B, SEC61G, TMCO1, CCDC47,
CC NCLN/Nicalin, NOMO and TMEM147; in the absence of ribosomes, only the
CC complex forms with NCLN/Nicalin, NOMO and TMEM147 remains intact
CC (PubMed:32820719). Participates in a large protein complex, which is
CC not related to the gamma-secretase complex (PubMed:15257293).
CC {ECO:0000269|PubMed:15257293, ECO:0000269|PubMed:20538592,
CC ECO:0000269|PubMed:32820719}.
CC -!- INTERACTION:
CC Q969V3; P42858: HTT; NbExp=9; IntAct=EBI-1056979, EBI-466029;
CC Q969V3; O76024: WFS1; NbExp=3; IntAct=EBI-1056979, EBI-720609;
CC Q969V3-2; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-10281480, EBI-3958099;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:15257293, ECO:0000269|PubMed:20538592}; Single-pass
CC membrane protein {ECO:0000269|PubMed:15257293,
CC ECO:0000269|PubMed:20538592}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q969V3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q969V3-2; Sequence=VSP_013851;
CC -!- TISSUE SPECIFICITY: Highly expressed in pancreas and skeletal muscle
CC and, at lower levels, in heart. {ECO:0000269|PubMed:15257293}.
CC -!- SIMILARITY: Belongs to the nicastrin family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH03076.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH25926.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAB66502.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK172848; BAD18812.1; -; mRNA.
DR EMBL; AC005331; AAC27667.1; -; Genomic_DNA.
DR EMBL; AC011547; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69330.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69333.1; -; Genomic_DNA.
DR EMBL; BC003076; AAH03076.2; ALT_INIT; mRNA.
DR EMBL; BC007275; AAH07275.1; -; mRNA.
DR EMBL; BC008920; AAH08920.2; -; mRNA.
DR EMBL; BC010064; AAH10064.2; -; mRNA.
DR EMBL; BC013283; AAH13283.2; -; mRNA.
DR EMBL; BC019091; AAH19091.2; -; mRNA.
DR EMBL; BC025926; AAH25926.1; ALT_INIT; mRNA.
DR EMBL; AL136567; CAB66502.1; ALT_INIT; mRNA.
DR EMBL; CR533566; CAG38597.1; -; mRNA.
DR EMBL; AL365369; CAB96945.1; -; mRNA.
DR CCDS; CCDS32869.1; -. [Q969V3-1]
DR RefSeq; NP_001308392.1; NM_001321463.1. [Q969V3-2]
DR RefSeq; NP_064555.2; NM_020170.3. [Q969V3-1]
DR PDB; 6W6L; EM; 3.84 A; 5=1-563.
DR PDBsum; 6W6L; -.
DR AlphaFoldDB; Q969V3; -.
DR SMR; Q969V3; -.
DR BioGRID; 121253; 217.
DR IntAct; Q969V3; 23.
DR MINT; Q969V3; -.
DR STRING; 9606.ENSP00000246117; -.
DR MEROPS; M28.978; -.
DR TCDB; 8.A.144.1.1; the nicalin (nicalin) family.
DR GlyConnect; 1566; 5 N-Linked glycans (1 site).
DR GlyGen; Q969V3; 3 sites, 4 N-linked glycans (1 site), 1 O-linked glycan (1 site).
DR iPTMnet; Q969V3; -.
DR MetOSite; Q969V3; -.
DR PhosphoSitePlus; Q969V3; -.
DR SwissPalm; Q969V3; -.
DR BioMuta; NCLN; -.
DR DMDM; 68052797; -.
DR EPD; Q969V3; -.
DR jPOST; Q969V3; -.
DR MassIVE; Q969V3; -.
DR MaxQB; Q969V3; -.
DR PaxDb; Q969V3; -.
DR PeptideAtlas; Q969V3; -.
DR PRIDE; Q969V3; -.
DR ProteomicsDB; 75850; -. [Q969V3-1]
DR ProteomicsDB; 75851; -. [Q969V3-2]
DR Antibodypedia; 1889; 145 antibodies from 32 providers.
DR DNASU; 56926; -.
DR Ensembl; ENST00000246117.9; ENSP00000246117.3; ENSG00000125912.11. [Q969V3-1]
DR GeneID; 56926; -.
DR KEGG; hsa:56926; -.
DR MANE-Select; ENST00000246117.9; ENSP00000246117.3; NM_020170.4; NP_064555.2.
DR UCSC; uc002lxi.4; human. [Q969V3-1]
DR CTD; 56926; -.
DR DisGeNET; 56926; -.
DR GeneCards; NCLN; -.
DR HGNC; HGNC:26923; NCLN.
DR HPA; ENSG00000125912; Low tissue specificity.
DR MIM; 609156; gene.
DR neXtProt; NX_Q969V3; -.
DR OpenTargets; ENSG00000125912; -.
DR PharmGKB; PA134898417; -.
DR VEuPathDB; HostDB:ENSG00000125912; -.
DR eggNOG; KOG2526; Eukaryota.
DR GeneTree; ENSGT00500000044945; -.
DR HOGENOM; CLU_034102_2_0_1; -.
DR InParanoid; Q969V3; -.
DR OMA; RMHQYDL; -.
DR OrthoDB; 424149at2759; -.
DR PhylomeDB; Q969V3; -.
DR TreeFam; TF105849; -.
DR PathwayCommons; Q969V3; -.
DR SignaLink; Q969V3; -.
DR BioGRID-ORCS; 56926; 35 hits in 1085 CRISPR screens.
DR ChiTaRS; NCLN; human.
DR GeneWiki; NCLN; -.
DR GenomeRNAi; 56926; -.
DR Pharos; Q969V3; Tbio.
DR PRO; PR:Q969V3; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q969V3; protein.
DR Bgee; ENSG00000125912; Expressed in mucosa of transverse colon and 125 other tissues.
DR ExpressionAtlas; Q969V3; baseline and differential.
DR Genevisible; Q969V3; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0043022; F:ribosome binding; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB.
DR GO; GO:0061635; P:regulation of protein complex stability; IDA:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:UniProtKB.
DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR InterPro; IPR016574; Nicalin.
DR InterPro; IPR007484; Peptidase_M28.
DR PANTHER; PTHR31826; PTHR31826; 1.
DR Pfam; PF04389; Peptidase_M28; 1.
DR PIRSF; PIRSF011018; Nicalin; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Endoplasmic reticulum; Glycoprotein;
KW Membrane; Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..42
FT /evidence="ECO:0000255"
FT CHAIN 43..563
FT /note="Nicalin"
FT /id="PRO_0000019687"
FT TOPO_DOM 43..522
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 523..543
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 544..563
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT CARBOHYD 241
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 428
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 446
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_013851"
FT VARIANT 214
FT /note="E -> D (in dbSNP:rs11671067)"
FT /id="VAR_050276"
FT VARIANT 551
FT /note="K -> R (in dbSNP:rs2288949)"
FT /evidence="ECO:0000269|PubMed:11230166, ECO:0000269|Ref.6"
FT /id="VAR_022552"
FT CONFLICT 19
FT /note="P -> L (in Ref. 6; CAG38597)"
FT /evidence="ECO:0000305"
FT CONFLICT 124
FT /note="V -> A (in Ref. 1; BAD18812)"
FT /evidence="ECO:0000305"
FT CONFLICT 207
FT /note="R -> W (in Ref. 6; CAG38597)"
FT /evidence="ECO:0000305"
FT CONFLICT 387
FT /note="H -> L (in Ref. 4; AAH03076)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 563 AA; 62974 MW; 5E74EDF6ABA6F44F CRC64;
MLEEAGEVLE NMLKASCLPL GFIVFLPAVL LLVAPPLPAA DAAHEFTVYR MQQYDLQGQP
YGTRNAVLNT EARTMAAEVL SRRCVLMRLL DFSYEQYQKA LRQSAGAVVI ILPRAMAAVP
QDVVRQFMEI EPEMLAMETA VPVYFAVEDE ALLSIYKQTQ AASASQGSAS AAEVLLRTAT
ANGFQMVTSG VQSKAVSDWL IASVEGRLTG LGGEDLPTIV IVAHYDAFGV APWLSLGADS
NGSGVSVLLE LARLFSRLYT YKRTHAAYNL LFFASGGGKF NYQGTKRWLE DNLDHTDSSL
LQDNVAFVLC LDTVGRGSSL HLHVSKPPRE GTLQHAFLRE LETVAAHQFP EVRFSMVHKR
INLAEDVLAW EHERFAIRRL PAFTLSHLES HRDGQRSSIM DVRSRVDSKT LTRNTRIIAE
ALTRVIYNLT EKGTPPDMPV FTEQMQIQQE QLDSVMDWLT NQPRAAQLVD KDSTFLSTLE
HHLSRYLKDV KQHHVKADKR DPEFVFYDQL KQVMNAYRVK PAVFDLLLAV GIAAYLGMAY
VAVQHFSLLY KTVQRLLVKA KTQ
