ID   TMM33_HUMAN             Reviewed;         247 AA.
AC   P57088; B3KSS8; Q9H953;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   19-SEP-2002, sequence version 2.
DT   27-MAR-2024, entry version 175.
DE   RecName: Full=Transmembrane protein 33;
DE   AltName: Full=Protein DB83;
DE   AltName: Full=SHINC-3 {ECO:0000303|PubMed:26268696};
GN   Name=TMEM33; Synonyms=DB83;
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=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   [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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
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   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RC   TISSUE=Melanoma;
RX   PubMed=17081065; DOI=10.1021/pr060363j;
RA   Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H., Mangini N.J.,
RA   Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R., Yamagishi S.,
RA   Shabanowitz J., Hearing V.J., Wu C., Appella E., Hunt D.F.;
RT   "Proteomic and bioinformatic characterization of the biogenesis and
RT   function of melanosomes.";
RL   J. Proteome Res. 5:3135-3144(2006).
RN   [6]
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   [7]
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=22223895; DOI=10.1074/mcp.m111.015131;
RA   Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA   Giglione C.;
RT   "Comparative large-scale characterisation of plant vs. mammal proteins
RT   reveals similar and idiosyncratic N-alpha acetylation features.";
RL   Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN   [8]
RP   IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION, AND
RP   INTERACTION WITH RTN1; RTN3; RTN3; RTN4 AND ARL6IP1.
RX   PubMed=25612671;
RA   Urade T., Yamamoto Y., Zhang X., Ku Y., Sakisaka T.;
RT   "Identification and characterization of TMEM33 as a reticulon-binding
RT   protein.";
RL   Kobe J. Med. Sci. 60:E57-E65(2014).
RN   [9]
RP   FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, INTERACTION WITH EIF2AK3, TISSUE
RP   SPECIFICITY, AND INDUCTION.
RX   PubMed=26268696; DOI=10.1007/s10549-015-3536-7;
RA   Sakabe I., Hu R., Jin L., Clarke R., Kasid U.N.;
RT   "TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein
RT   and modulator of the unfolded protein response signaling.";
RL   Breast Cancer Res. Treat. 153:285-297(2015).
RN   [10]
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   [11]
RP   FUNCTION.
RX   PubMed=30760708; DOI=10.1038/s41467-019-08590-7;
RA   Savage A.M., Kurusamy S., Chen Y., Jiang Z., Chhabria K., MacDonald R.B.,
RA   Kim H.R., Wilson H.L., van Eeden F.J.M., Armesilla A.L., Chico T.J.A.,
RA   Wilkinson R.N.;
RT   "tmem33 is essential for VEGF-mediated endothelial calcium oscillations and
RT   angiogenesis.";
RL   Nat. Commun. 10:732-732(2019).
RN   [12]
RP   FUNCTION, AND INTERACTION WITH RNF26.
RX   PubMed=32614325; DOI=10.7554/elife.57306;
RA   Fenech E.J., Lari F., Charles P.D., Fischer R., Laetitia-Thezenas M.,
RA   Bagola K., Paton A.W., Paton J.C., Gyrd-Hansen M., Kessler B.M.,
RA   Christianson J.C.;
RT   "Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies
RT   modulators of innate immune signalling.";
RL   Elife 9:0-0(2020).
RN   [13]
RP   FUNCTION, AND INTERACTION WITH RNF5.
RX   PubMed=34487377; DOI=10.15252/embj.2021108065;
RA   Liu F., Ma M., Gao A., Ma F., Ma G., Liu P., Jia C., Wang Y., Donahue K.,
RA   Zhang S., Ong I.M., Keles S., Li L., Xu W.;
RT   "PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by
RT   controlling SCAP stability.";
RL   EMBO J. 0:0-0(2021).
CC   -!- FUNCTION: Acts as a regulator of the tubular endoplasmic reticulum (ER)
CC       network by modulating intracellular calcium homeostasis.
CC       Mechanistically, stimulates PKD2 calcium-dependent activity (By
CC       similarity). Suppresses the RTN3/4-induced formation of the ER tubules
CC       (PubMed:25612671). Positively regulates PERK-mediated and IRE1-mediated
CC       unfolded protein response signaling (PubMed:26268696). Plays an
CC       essential role in VEGF-mediated release of Ca(2+) from ER stores during
CC       angiogenesis (PubMed:30760708). Also plays a role in the modulation of
CC       innate immune signaling through the cGAS-STING pathway by interacting
CC       with RNF26 (PubMed:32614325). Participates in lipid metabolism by
CC       acting as a downstream effector of the pyruvate kinase/PKM. Forms a
CC       complex with RNF5 to facilitate polyubiquitination and subsequent
CC       degradation of SCAP on the ER membrane (PubMed:34487377).
CC       {ECO:0000250|UniProtKB:Q9CR67, ECO:0000269|PubMed:25612671,
CC       ECO:0000269|PubMed:26268696, ECO:0000269|PubMed:30760708,
CC       ECO:0000269|PubMed:32614325, ECO:0000269|PubMed:34487377}.
CC   -!- SUBUNIT: Interacts with EIF2AK3 (PubMed:26268696). Interacts with
CC       ARL6IP1, isoform RTN1-A of RTN1, isoform RTN2-B of RTN2, isoform 3 of
CC       RTN3 and isoform 3 of RTN4 (PubMed:25612671). Interacts with RNF5
CC       (PubMed:34487377). Interacts with RNF26 (PubMed:32614325). Interacts
CC       with PKD2 (By similarity). {ECO:0000250|UniProtKB:Q9CR67,
CC       ECO:0000269|PubMed:25612671, ECO:0000269|PubMed:26268696,
CC       ECO:0000269|PubMed:32614325, ECO:0000269|PubMed:34487377}.
CC   -!- INTERACTION:
CC       P57088; P48039: MTNR1A; NbExp=3; IntAct=EBI-1048629, EBI-1188238;
CC       P57088; Q96FB2; NbExp=3; IntAct=EBI-1048629, EBI-2857623;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:25612671, ECO:0000269|PubMed:26268696}; Multi-pass
CC       membrane protein {ECO:0000255}. Melanosome
CC       {ECO:0000269|PubMed:17081065}. Nucleus envelope
CC       {ECO:0000269|PubMed:25612671}. Note=Identified by mass spectrometry in
CC       melanosome fractions from stage I to stage IV. Co-localizes with RTN4
CC       at the ER sheets. {ECO:0000269|PubMed:17081065,
CC       ECO:0000269|PubMed:25612671}.
CC   -!- TISSUE SPECIFICITY: Prostate cancer and several cancer cell lines (at
CC       protein level). Widely expressed. Expressed at higher levels in
CC       endocrine-resistant breast cancer cells as compared to endocrine-
CC       sensitive breast cancer cells. Expressed at higher levels in early
CC       recurrence breast cancer tissues as compared to non-recurrent breast
CC       tumors. {ECO:0000269|PubMed:26268696}.
CC   -!- INDUCTION: By endoplasmic reticulum (ER) stress.
CC       {ECO:0000269|PubMed:26268696}.
CC   -!- SIMILARITY: Belongs to the PER33/POM33 family. {ECO:0000305}.
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DR   EMBL; AK001387; BAA91665.1; -; mRNA.
DR   EMBL; AK023062; BAB14384.1; -; mRNA.
DR   EMBL; AK094190; BAG52840.1; -; mRNA.
DR   EMBL; CR457260; CAG33541.1; -; mRNA.
DR   EMBL; CH471069; EAW92991.1; -; Genomic_DNA.
DR   EMBL; BC000948; AAH00948.2; -; mRNA.
DR   CCDS; CCDS3464.1; -.
DR   RefSeq; NP_060596.2; NM_018126.2.
DR   RefSeq; XP_005248173.1; XM_005248116.3.
DR   RefSeq; XP_005248174.1; XM_005248117.2.
DR   AlphaFoldDB; P57088; -.
DR   SMR; P57088; -.
DR   BioGRID; 120462; 168.
DR   IntAct; P57088; 69.
DR   MINT; P57088; -.
DR   STRING; 9606.ENSP00000422473; -.
DR   TCDB; 8.A.124.1.3; the tetra spanning protein 1 (tts1) family.
DR   GlyGen; P57088; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P57088; -.
DR   PhosphoSitePlus; P57088; -.
DR   SwissPalm; P57088; -.
DR   BioMuta; TMEM33; -.
DR   DMDM; 23503056; -.
DR   EPD; P57088; -.
DR   jPOST; P57088; -.
DR   MassIVE; P57088; -.
DR   MaxQB; P57088; -.
DR   PaxDb; 9606-ENSP00000422473; -.
DR   PeptideAtlas; P57088; -.
DR   ProteomicsDB; 56997; -.
DR   Pumba; P57088; -.
DR   TopDownProteomics; P57088; -.
DR   Antibodypedia; 60901; 97 antibodies from 19 providers.
DR   DNASU; 55161; -.
DR   Ensembl; ENST00000504986.6; ENSP00000422473.1; ENSG00000109133.14.
DR   Ensembl; ENST00000513702.5; ENSP00000427006.1; ENSG00000109133.14.
DR   GeneID; 55161; -.
DR   KEGG; hsa:55161; -.
DR   MANE-Select; ENST00000504986.6; ENSP00000422473.1; NM_018126.3; NP_060596.2.
DR   UCSC; uc003gwi.3; human.
DR   AGR; HGNC:25541; -.
DR   CTD; 55161; -.
DR   DisGeNET; 55161; -.
DR   GeneCards; TMEM33; -.
DR   HGNC; HGNC:25541; TMEM33.
DR   HPA; ENSG00000109133; Low tissue specificity.
DR   MIM; 618515; gene.
DR   neXtProt; NX_P57088; -.
DR   OpenTargets; ENSG00000109133; -.
DR   PharmGKB; PA134963055; -.
DR   VEuPathDB; HostDB:ENSG00000109133; -.
DR   eggNOG; KOG4002; Eukaryota.
DR   GeneTree; ENSGT00390000011368; -.
DR   InParanoid; P57088; -.
DR   OMA; FFSIRPT; -.
DR   OrthoDB; 2878359at2759; -.
DR   PhylomeDB; P57088; -.
DR   TreeFam; TF314068; -.
DR   PathwayCommons; P57088; -.
DR   SignaLink; P57088; -.
DR   BioGRID-ORCS; 55161; 11 hits in 1155 CRISPR screens.
DR   ChiTaRS; TMEM33; human.
DR   GenomeRNAi; 55161; -.
DR   Pharos; P57088; Tbio.
DR   PRO; PR:P57088; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; P57088; Protein.
DR   Bgee; ENSG00000109133; Expressed in adrenal tissue and 202 other cell types or tissues.
DR   ExpressionAtlas; P57088; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:AgBase.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0042470; C:melanosome; IDA:UniProtKB.
DR   GO; GO:0005635; C:nuclear envelope; IDA:AgBase.
DR   GO; GO:0071786; P:endoplasmic reticulum tubular network organization; IBA:GO_Central.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR   GO; GO:0061024; P:membrane organization; IBA:GO_Central.
DR   GO; GO:1903896; P:positive regulation of IRE1-mediated unfolded protein response; IDA:UniProtKB.
DR   GO; GO:1903899; P:positive regulation of PERK-mediated unfolded protein response; IDA:UniProtKB.
DR   GO; GO:1903371; P:regulation of endoplasmic reticulum tubular network organization; IDA:UniProtKB.
DR   GO; GO:0034976; P:response to endoplasmic reticulum stress; IDA:UniProtKB.
DR   InterPro; IPR005344; TMEM33/Pom33.
DR   PANTHER; PTHR12703; TRANSMEMBRANE PROTEIN 33; 1.
DR   PANTHER; PTHR12703:SF4; TRANSMEMBRANE PROTEIN 33; 1.
DR   Pfam; PF03661; TMEM33_Pom33; 1.
DR   Genevisible; P57088; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Endoplasmic reticulum; Immunity; Innate immunity; Membrane;
KW   Nucleus; Reference proteome; Transmembrane; Transmembrane helix.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0007744|PubMed:22223895"
FT   CHAIN           2..247
FT                   /note="Transmembrane protein 33"
FT                   /id="PRO_0000220899"
FT   TOPO_DOM        2..31
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000305|PubMed:26268696"
FT   TRANSMEM        32..52
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        53..100
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305|PubMed:26268696"
FT   TRANSMEM        101..121
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        122..155
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000305|PubMed:26268696"
FT   TRANSMEM        156..176
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        177..247
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305|PubMed:26268696"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0007744|PubMed:22223895"
FT   CONFLICT        7
FT                   /note="N -> S (in Ref. 1; BAA91665)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   247 AA;  27978 MW;  392A53377511A6A0 CRC64;
     MADTTPNGPQ GAGAVQFMMT NKLDTAMWLS RLFTVYCSAL FVLPLLGLHE AASFYQRALL
     ANALTSALRL HQRLPHFQLS RAFLAQALLE DSCHYLLYSL IFVNSYPVTM SIFPVLLFSL
     LHAATYTKKV LDARGSNSLP LLRSVLDKLS ANQQNILKFI ACNEIFLMPA TVFMLFSGQG
     SLLQPFIYYR FLTLRYSSRR NPYCRTLFNE LRIVVEHIIM KPACPLFVRR LCLQSIAFIS
     RLAPTVP
//