T4S20_HUMAN
ID T4S20_HUMAN Reviewed; 229 AA.
AC Q53R12; B2RP42; Q5U609; Q6UWS1; Q9H5X9;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 24-MAY-2005, sequence version 1.
DT 03-AUG-2022, entry version 116.
DE RecName: Full=Transmembrane 4 L6 family member 20;
GN Name=TM4SF20; ORFNames=UNQ518/PRO994;
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=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-27.
RC TISSUE=Ileal mucosa;
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=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-27.
RC TISSUE=Colon;
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, TISSUE SPECIFICITY, AND INVOLVEMENT IN SLI5.
RX PubMed=23810381; DOI=10.1016/j.ajhg.2013.05.027;
RA Wiszniewski W., Hunter J.V., Hanchard N.A., Willer J.R., Shaw C., Tian Q.,
RA Illner A., Wang X., Cheung S.W., Patel A., Campbell I.M., Hixson P.,
RA Ester A.R., Azamian M.S., Potocki L., Zapata G., Hernandez P.P.,
RA Ramocki M.B., Santos-Cortez R.L., Wang G., York M.K., Justice M.J.,
RA Chu Z.D., Bader P.I., Omo-Griffith L., Madduri N.S., Scharer G.,
RA Crawford H.P., Yanatatsaneejit P., Eifert A., Kerr J., Bacino C.A.,
RA Franklin A.I., Goin-Kochel R.P., Simpson G., Immken L., Haque M.E.,
RA Stosic M., Williams M.D., Morgan T.M., Pruthi S., Omary R., Boyadjiev S.A.,
RA Win K.K., Thida A., Hurles M., Hibberd M.L., Khor C.C., Van Vinh Chau N.,
RA Gallagher T.E., Mutirangura A., Stankiewicz P., Beaudet A.L.,
RA Maletic-Savatic M., Rosenfeld J.A., Shaffer L.G., Davis E.E., Belmont J.W.,
RA Dunstan S., Simmons C.P., Bonnen P.E., Leal S.M., Katsanis N., Lupski J.R.,
RA Lalani S.R.;
RT "TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of
RT early language delay and cerebral white matter hyperintensities.";
RL Am. J. Hum. Genet. 93:197-210(2013).
RN [6]
RP INDUCTION, AND FUNCTION.
RX PubMed=25310401; DOI=10.1371/journal.pone.0108528;
RA Chen Q., Lee C.E., Denard B., Ye J.;
RT "Sustained induction of collagen synthesis by TGF-beta requires regulated
RT intramembrane proteolysis of CREB3L1.";
RL PLoS ONE 9:E108528-E108528(2014).
RN [7]
RP FUNCTION, DOMAIN, SUBCELLULAR LOCATION, GLYCOSYLATION, PROTEOLYTIC
RP PROCESSING, AND MUTAGENESIS OF GLY-12; PHE-13; SER-14; LEU-15; LEU-16;
RP GLY-22; ASN-26; ASN-80; ASN-132; ASN-148 AND ASN-163.
RX PubMed=27499293; DOI=10.1016/j.molcel.2016.06.032;
RA Chen Q., Denard B., Lee C.E., Han S., Ye J.S., Ye J.;
RT "Inverting the topology of a transmembrane protein by regulating the
RT translocation of the first transmembrane helix.";
RL Mol. Cell 63:567-578(2016).
CC -!- FUNCTION: Polytopic transmembrane protein that inhibits regulated
CC intramembrane proteolysis (RIP) of CREB3L1, inhibiting its activation
CC and the induction of collagen synthesis (PubMed:25310401,
CC PubMed:27499293). In response to ceramide, which alters TM4SF20
CC membrane topology, stimulates RIP activation of CREB3L1
CC (PubMed:27499293). Ceramide reverses the direction through which
CC transmembrane helices are translocated into the endoplasmic reticulum
CC membrane during translation of TM4SF20, this mechanism is called
CC 'regulated alternative translocation' (RAT) and regulates the function
CC of the transmembrane protein (PubMed:27499293).
CC {ECO:0000269|PubMed:25310401, ECO:0000269|PubMed:27499293}.
CC -!- INTERACTION:
CC Q53R12; Q9NZG7: NINJ2; NbExp=3; IntAct=EBI-1805798, EBI-10317425;
CC Q53R12; Q15836: VAMP3; NbExp=3; IntAct=EBI-1805798, EBI-722343;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:23810381}; Multi-
CC pass membrane protein {ECO:0000269|PubMed:23810381}. Endoplasmic
CC reticulum membrane {ECO:0000269|PubMed:25310401}; Multi-pass membrane
CC protein {ECO:0000269|PubMed:25310401}. Note=Ceramide alters the
CC direction through which transmembrane helices are translocated into the
CC endoplasmic reticulum membrane during translation of TM4SF20.
CC {ECO:0000269|PubMed:27499293}.
CC -!- TISSUE SPECIFICITY: Expressed in the brain, with high levels in the
CC parietal lobe, hippocampus, pons, white matter and cerebellum.
CC {ECO:0000269|PubMed:23810381}.
CC -!- INDUCTION: TGFB1 inhibits TM4SF20 expression to activate CREB3L1
CC (PubMed:25310401). {ECO:0000269|PubMed:25310401}.
CC -!- DOMAIN: The first transmembrane helix plays a critical role for the
CC insertion orientation in the endoplasmic reticulum membrane.
CC {ECO:0000269|PubMed:27499293}.
CC -!- PTM: Glycosylated at Asn-132, Asn-148 and Asn-163 in presence of
CC ceramide which inverts the orientation of TM4SF20 in membranes exposing
CC these residues to the endoplasmic reticulum lumen.
CC {ECO:0000269|PubMed:27499293}.
CC -!- PTM: Cleaved by signal peptidase at Ser-14 but the peptide does not act
CC as a signal peptide. Cleavage is inhibited by ceramide which inverts
CC the orientation of TM4SF20 in membranes exposing the N-terminus to the
CC cytosol and not to the endoplasmic reticulum lumen.
CC {ECO:0000269|PubMed:27499293}.
CC -!- DISEASE: Specific language impairment 5 (SLI5) [MIM:615432]: A disorder
CC characterized by a delay in early speech acquisition. It is usually
CC associated with cerebral white matter abnormalities on brain MRI. Some
CC individuals may show disorders in communication, consistent with autism
CC spectrum disorder, or global developmental delay, although others
CC ultimately show normal cognitive function. Penetrance is incomplete and
CC expressivity is variable. {ECO:0000269|PubMed:23810381}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the L6 tetraspanin family. {ECO:0000305}.
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DR EMBL; AY358671; AAQ89034.1; -; mRNA.
DR EMBL; AK026453; BAB15488.1; -; mRNA.
DR EMBL; AC097662; AAY24253.1; -; Genomic_DNA.
DR EMBL; BC035754; AAH35754.1; -; mRNA.
DR EMBL; BC137256; AAI37257.1; -; mRNA.
DR EMBL; BC137257; AAI37258.1; -; mRNA.
DR CCDS; CCDS2466.1; -.
DR RefSeq; NP_079071.2; NM_024795.4.
DR AlphaFoldDB; Q53R12; -.
DR BioGRID; 122943; 18.
DR IntAct; Q53R12; 11.
DR STRING; 9606.ENSP00000303028; -.
DR TCDB; 8.A.75.1.4; the transmembrane 4 l6 (tm4l6) family.
DR PhosphoSitePlus; Q53R12; -.
DR BioMuta; TM4SF20; -.
DR DMDM; 74726514; -.
DR MassIVE; Q53R12; -.
DR MaxQB; Q53R12; -.
DR PaxDb; Q53R12; -.
DR PeptideAtlas; Q53R12; -.
DR PRIDE; Q53R12; -.
DR ProteomicsDB; 62514; -.
DR ABCD; Q53R12; 4 sequenced antibodies.
DR Antibodypedia; 47680; 65 antibodies from 15 providers.
DR DNASU; 79853; -.
DR Ensembl; ENST00000304568.4; ENSP00000303028.3; ENSG00000168955.4.
DR GeneID; 79853; -.
DR KEGG; hsa:79853; -.
DR MANE-Select; ENST00000304568.4; ENSP00000303028.3; NM_024795.4; NP_079071.2.
DR UCSC; uc002vpb.3; human.
DR CTD; 79853; -.
DR DisGeNET; 79853; -.
DR GeneCards; TM4SF20; -.
DR HGNC; HGNC:26230; TM4SF20.
DR HPA; ENSG00000168955; Tissue enriched (intestine).
DR MalaCards; TM4SF20; -.
DR MIM; 615404; gene.
DR MIM; 615432; phenotype.
DR neXtProt; NX_Q53R12; -.
DR OpenTargets; ENSG00000168955; -.
DR PharmGKB; PA142670803; -.
DR VEuPathDB; HostDB:ENSG00000168955; -.
DR eggNOG; ENOG502RZTZ; Eukaryota.
DR GeneTree; ENSGT01030000234590; -.
DR HOGENOM; CLU_105103_0_0_1; -.
DR InParanoid; Q53R12; -.
DR OMA; FDLQWFF; -.
DR OrthoDB; 1322314at2759; -.
DR PhylomeDB; Q53R12; -.
DR TreeFam; TF331371; -.
DR PathwayCommons; Q53R12; -.
DR SignaLink; Q53R12; -.
DR BioGRID-ORCS; 79853; 12 hits in 1062 CRISPR screens.
DR GenomeRNAi; 79853; -.
DR Pharos; Q53R12; Tbio.
DR PRO; PR:Q53R12; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q53R12; protein.
DR Bgee; ENSG00000168955; Expressed in jejunal mucosa and 57 other tissues.
DR ExpressionAtlas; Q53R12; baseline and differential.
DR Genevisible; Q53R12; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; IDA:HPA.
DR GO; GO:0016021; C:integral component of membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0045861; P:negative regulation of proteolysis; IDA:UniProtKB.
DR InterPro; IPR008661; L6_membrane.
DR PANTHER; PTHR14198; PTHR14198; 1.
DR Pfam; PF05805; L6_membrane; 1.
PE 1: Evidence at protein level;
KW Autism spectrum disorder; Endoplasmic reticulum; Membrane;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..229
FT /note="Transmembrane 4 L6 family member 20"
FT /id="PRO_0000251228"
FT TOPO_DOM 1..14
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 15..35
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 36..44
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 45..65
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 66..83
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 84..104
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 105..185
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 186..206
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 207..229
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT SITE 13..14
FT /note="Cleavage"
FT /evidence="ECO:0000269|PubMed:27499293"
FT VARIANT 27
FT /note="A -> V (in dbSNP:rs7574414)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_027673"
FT MUTAGEN 12
FT /note="G->P: No effect on cleavage of the first 13
FT residues."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 13
FT /note="F->P: No effect on cleavage of the first 13
FT residues."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 14
FT /note="S->P: Abolishes cleavage of the first 13 residues."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 15
FT /note="L->P: No effect on cleavage of the first 13
FT residues."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 16
FT /note="L->P: No effect on cleavage of the first 13
FT residues."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 22
FT /note="G->L: Inverts transmembrane topology. Induces
FT cleavage of CREB3L1."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 26
FT /note="N->L: Inverts transmembrane topology."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 80
FT /note="N->Q: No effect on glycosylation upon ceramide
FT treatment."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 132
FT /note="N->Q: Reduces glycosylation upon ceramide treatment.
FT Abolishes glycosylation upon ceramide treatment; when
FT associated with Q-132 and Q-163."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 148
FT /note="N->Q: Reduces glycosylation upon ceramide treatment.
FT Abolishes glycosylation upon ceramide treatment; when
FT associated with Q-132 and Q-163."
FT /evidence="ECO:0000269|PubMed:27499293"
FT MUTAGEN 163
FT /note="N->Q: Reduces glycosylation upon ceramide treatment.
FT Abolishes glycosylation upon ceramide treatment; when
FT associated with Q-132 and Q-148."
FT /evidence="ECO:0000269|PubMed:27499293"
FT CONFLICT 89
FT /note="L -> F (in Ref. 1; AAQ89034 and 4; AAH35754)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 229 AA; 25075 MW; 1718E0594997A1A1 CRC64;
MTCCEGWTSC NGFSLLVLLL LGVVLNAIPL IVSLVEEDQF SQNPISCFEW WFPGIIGAGL
MAIPATTMSL TARKRACCNN RTGMFLSSLF SVITVIGALY CMLISIQALL KGPLMCNSPS
NSNANCEFSL KNISDIHPES FNLQWFFNDS CAPPTGFNKP TSNDTMASGW RASSFHFDSE
ENKHRLIHFS VFLGLLLVGI LEVLFGLSQI VIGFLGCLCG VSKRRSQIV
