SPPL3_MOUSE
ID SPPL3_MOUSE Reviewed; 384 AA.
AC Q9CUS9; E9QP88; Q8R597;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=Signal peptide peptidase-like 3 {ECO:0000250|UniProtKB:Q8TCT6};
DE Short=SPP-like 3 {ECO:0000250|UniProtKB:Q8TCT6};
DE EC=3.4.23.-;
DE AltName: Full=Intramembrane protease 2 {ECO:0000250|UniProtKB:Q8TCT6};
DE Short=IMP-2 {ECO:0000250|UniProtKB:Q8TCT6};
DE AltName: Full=Presenilin-like protein 4 {ECO:0000250|UniProtKB:Q8TCT6};
GN Name=Sppl3 {ECO:0000250|UniProtKB:Q8TCT6, ECO:0000312|MGI:MGI:1891433};
GN Synonyms=Imp2 {ECO:0000250|UniProtKB:Q8TCT6},
GN Psl4 {ECO:0000250|UniProtKB:Q8TCT6}, Usmg3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Head;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 107-384.
RC TISSUE=Mammary tumor;
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 DISRUPTION PHENOTYPE.
RX PubMed=20562862; DOI=10.1038/nbt.1644;
RA Tang T., Li L., Tang J., Li Y., Lin W.Y., Martin F., Grant D., Solloway M.,
RA Parker L., Ye W., Forrest W., Ghilardi N., Oravecz T., Platt K.A.,
RA Rice D.S., Hansen G.M., Abuin A., Eberhart D.E., Godowski P., Holt K.H.,
RA Peterson A., Zambrowicz B.P., de Sauvage F.J.;
RT "A mouse knockout library for secreted and transmembrane proteins.";
RL Nat. Biotechnol. 28:749-755(2010).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25354954; DOI=10.15252/embj.201488375;
RA Voss M., Kunzel U., Higel F., Kuhn P.H., Colombo A., Fukumori A.,
RA Haug-Kroper M., Klier B., Grammer G., Seidl A., Schroder B., Obst R.,
RA Steiner H., Lichtenthaler S.F., Haass C., Fluhrer R.;
RT "Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3
RT (SPPL3) regulates cellular N-glycosylation.";
RL EMBO J. 33:2890-2905(2014).
RN [6]
RP FUNCTION, INTERACTION WITH STIM1, AND MUTAGENESIS OF ASP-200 AND ASP-271.
RX PubMed=25384971; DOI=10.1128/mcb.01124-14;
RA Makowski S.L., Wang Z., Pomerantz J.L.;
RT "A protease-independent function for SPPL3 in NFAT activation.";
RL Mol. Cell. Biol. 35:451-467(2015).
RN [7]
RP FUNCTION.
RX PubMed=25827571; DOI=10.1074/mcp.m115.048298;
RA Kuhn P.H., Voss M., Haug-Kroper M., Schroder B., Schepers U., Brase S.,
RA Haass C., Lichtenthaler S.F., Fluhrer R.;
RT "Secretome analysis identifies novel signal peptide peptidase-like 3
RT (SPPL3) substrates and reveals a role of SPPL3 in multiple Golgi
RT glycosylation pathways.";
RL Mol. Cell. Proteomics 14:1584-1598(2015).
CC -!- FUNCTION: Intramembrane-cleaving aspartic protease (I-CLiP) that
CC cleaves type II membrane protein substrates in or close to their
CC luminal transmembrane domain boundaries. Acts like a sheddase by
CC mediating the proteolytic release and secretion of active site-
CC containing ectodomains of glycan-modifiying glycosidase and
CC glycosyltransferase enzymes such as MGAT5, B4GAT1 and B4GALT1
CC (PubMed:25354954, PubMed:25827571). Plays a role in the regulation of
CC cellular glycosylation processes (PubMed:25354954). Required to link T-
CC cell antigen receptor (TCR) and calcineurin-NFAT signaling cascades in
CC lymphocytes by promoting the association of STIM1 and ORAI1 during
CC store-operated calcium entry (SOCE) in a protease-independent manner
CC (PubMed:25384971). {ECO:0000269|PubMed:25354954,
CC ECO:0000269|PubMed:25384971, ECO:0000269|PubMed:25827571}.
CC -!- ACTIVITY REGULATION: Its proteolytic activity is blocked by a signal
CC peptide peptidase (SPP) inhibitor, (ZLL)2-ketone (ZLL) or a gamma-
CC secretase inhibitor, LY411,575. {ECO:0000250|UniProtKB:Q8TCT6}.
CC -!- SUBUNIT: Monomer. Homodimer (By similarity). Interacts with STIM1 (via
CC transmembrane region and SOAR/CAD domain); the interaction promotes the
CC binding of STIM1 to ORAI1 (PubMed:25384971).
CC {ECO:0000250|UniProtKB:Q8TCT6, ECO:0000269|PubMed:25384971}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q8TCT6}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q8TCT6}. Golgi apparatus
CC {ECO:0000250|UniProtKB:Q8TCT6}. Membrane
CC {ECO:0000250|UniProtKB:Q8TCT6}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q8TCT6}; Lumenal side
CC {ECO:0000250|UniProtKB:Q8TCT6}.
CC -!- DOMAIN: The first transmembrane domain may act as a type I signal
CC anchor. The catalytic loops is exposed toward the lumen. The PAL motif
CC is required for normal active site conformation. The catalytic domains
CC embedded in the membrane are in the opposite orientation to that of the
CC presenilin protein family. {ECO:0000250|UniProtKB:P49768,
CC ECO:0000250|UniProtKB:Q8TCT6}.
CC -!- PTM: Not glycosylated. {ECO:0000250|UniProtKB:Q8TCT6}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable but display growth retardation
CC and haematologic abnormalities (PubMed:20562862). Male are sterile
CC (PubMed:20562862). Exhibit hyperglycosylation of cellular glycoproteins
CC (PubMed:25354954). {ECO:0000269|PubMed:20562862,
CC ECO:0000269|PubMed:25354954}.
CC -!- SIMILARITY: Belongs to the peptidase A22B family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB29515.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK014709; BAB29515.1; ALT_INIT; mRNA.
DR EMBL; AC117799; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC119205; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC023131; AAH23131.2; -; mRNA.
DR CCDS; CCDS19578.1; -.
DR RefSeq; NP_083288.2; NM_029012.2.
DR AlphaFoldDB; Q9CUS9; -.
DR STRING; 10090.ENSMUSP00000031530; -.
DR MEROPS; A22.005; -.
DR PhosphoSitePlus; Q9CUS9; -.
DR EPD; Q9CUS9; -.
DR MaxQB; Q9CUS9; -.
DR PaxDb; Q9CUS9; -.
DR PRIDE; Q9CUS9; -.
DR ProteomicsDB; 261625; -.
DR Antibodypedia; 31508; 113 antibodies from 21 providers.
DR DNASU; 74585; -.
DR Ensembl; ENSMUST00000031530; ENSMUSP00000031530; ENSMUSG00000029550.
DR GeneID; 74585; -.
DR KEGG; mmu:74585; -.
DR UCSC; uc008zda.1; mouse.
DR CTD; 121665; -.
DR MGI; MGI:1891433; Sppl3.
DR VEuPathDB; HostDB:ENSMUSG00000029550; -.
DR eggNOG; KOG2443; Eukaryota.
DR GeneTree; ENSGT00940000158101; -.
DR HOGENOM; CLU_061449_0_0_1; -.
DR InParanoid; Q9CUS9; -.
DR OMA; PCSDGNK; -.
DR OrthoDB; 1087991at2759; -.
DR PhylomeDB; Q9CUS9; -.
DR TreeFam; TF323842; -.
DR BRENDA; 3.4.23.B24; 3474.
DR BioGRID-ORCS; 74585; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Sppl3; mouse.
DR PRO; PR:Q9CUS9; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q9CUS9; protein.
DR Bgee; ENSMUSG00000029550; Expressed in floor plate of midbrain and 258 other tissues.
DR ExpressionAtlas; Q9CUS9; baseline and differential.
DR Genevisible; Q9CUS9; MM.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0030660; C:Golgi-associated vesicle membrane; ISS:UniProtKB.
DR GO; GO:0071458; C:integral component of cytoplasmic side of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0071556; C:integral component of lumenal side of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0005791; C:rough endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0033619; P:membrane protein proteolysis; ISS:UniProtKB.
DR GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IDA:UniProtKB.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IDA:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:UniProtKB.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; ISS:UniProtKB.
DR GO; GO:0006465; P:signal peptide processing; IBA:GO_Central.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IDA:UniProtKB.
DR InterPro; IPR007369; Peptidase_A22B_SPP.
DR InterPro; IPR006639; Preselin/SPP.
DR PANTHER; PTHR12174; PTHR12174; 1.
DR Pfam; PF04258; Peptidase_A22B; 1.
DR SMART; SM00730; PSN; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Golgi apparatus; Hydrolase; Membrane; Protease;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..384
FT /note="Signal peptide peptidase-like 3"
FT /id="PRO_0000073913"
FT TOPO_DOM 1..8
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT6"
FT TRANSMEM 9..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 30..73
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT6"
FT TRANSMEM 74..94
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 95
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 96..116
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 117..138
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 139..159
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 160..164
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 165..185
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 186..190
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 191..211
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 212..262
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT6"
FT TRANSMEM 263..283
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 284..311
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 312..332
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 333..339
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 340..360
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 361..384
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8TCT6"
FT MOTIF 341..343
FT /note="PAL"
FT ACT_SITE 200
FT /evidence="ECO:0000250|UniProtKB:P49810"
FT ACT_SITE 271
FT /evidence="ECO:0000250|UniProtKB:P49810"
FT MUTAGEN 200
FT /note="D->A: Does not inhibit NFAT-induced transcription
FT activation."
FT /evidence="ECO:0000269|PubMed:25384971"
FT MUTAGEN 271
FT /note="D->A: Does not inhibit NFAT-induced transcription
FT activation."
FT /evidence="ECO:0000269|PubMed:25384971"
FT CONFLICT 181
FT /note="V -> D (in Ref. 1; BAB29515)"
FT /evidence="ECO:0000305"
FT CONFLICT 233
FT /note="R -> K (in Ref. 1; BAB29515)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 384 AA; 42261 MW; 04D8C036355B32A1 CRC64;
MAEQTYSWAY SLVDSSQVST FLISILLIVY GSFRSLNMDF ENQDKEKDSN SSSGSFNGNS
TNNSIQTIDS TQALFLPIGA SVSLLVMFFF FDSVQVVFTI CTAVLATIAF AFLLLPMCQY
LTRPCSPQNK ISFGCCGRFT AAELLSFSLS VMLVLIWVLT GHWLLMDALA MGLCVAMIAF
VRLPSLKVSC LLLSGLLIYD VFWVFFSAYI FNSNVMVKVA TQPADNPLDV LSRKLHLGPN
VGRDVPRLSL PGKLVFPSST GSHFSMLGIG DIVMPGLLLC FVLRYDNYKK QASGDSCGAP
GPANISGRMQ KVSYFHCTLI GYFVGLLTAT VASRIHRAAQ PALLYLVPFT LLPLLTMAYL
KGDLRRMWSE PFHSKSSSSR FLEV
