S15A4_RAT
ID S15A4_RAT Reviewed; 572 AA.
AC O09014; Q5M931;
DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Solute carrier family 15 member 4 {ECO:0000305};
DE AltName: Full=Peptide/histidine transporter 1 {ECO:0000303|PubMed:9092568};
DE Short=rPHT1 {ECO:0000303|PubMed:9092568};
GN Name=Slc15a4 {ECO:0000312|RGD:708469};
GN Synonyms=Pht1 {ECO:0000303|PubMed:9092568};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND TRANSPORTER ACTIVITY.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=9092568; DOI=10.1074/jbc.272.15.10205;
RA Yamashita T., Shimada S., Guo W., Sato K., Kohmura E., Hayakawa T.,
RA Takagi T., Tohyama M.;
RT "Cloning and functional expression of a brain peptide/histidine
RT transporter.";
RL J. Biol. Chem. 272:10205-10211(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [3]
RP TISSUE SPECIFICITY.
RX PubMed=11741260; DOI=10.1208/ps030109;
RA Herrera-Ruiz D., Wang Q., Gudmundsson O.S., Cook T.J., Smith R.L.,
RA Faria T.N., Knipp G.T.;
RT "Spatial expression patterns of peptide transporters in the human and rat
RT gastrointestinal tracts, Caco-2 in vitro cell culture model, and multiple
RT human tissues.";
RL AAPS PharmSci 3:E9-E9(2001).
CC -!- FUNCTION: Proton-coupled amino-acid transporter that mediates the
CC transmembrane transport of L-histidine and some di- and tripeptides
CC from inside the lysosome to the cytosol, and plays a key role in innate
CC immune response (PubMed:9092568). Able to transport a variety of
CC di- and tripeptides, including carnosine and some peptidoglycans (By
CC similarity). Transporter activity is pH-dependent and maximized in the
CC acidic lysosomal environment (PubMed:9092568). Involved in the
CC detection of microbial pathogens by toll-like receptors (TLRs) and NOD-
CC like receptors (NLRs), probably by mediating transport of bacterial
CC peptidoglycans across the endolysosomal membrane: catalyzes the
CC transport of certain bacterial peptidoglycans, such as muramyl
CC dipeptide (MDP), the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-
CC 2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand. Required for TLR7,
CC TLR8 and TLR9-mediated type I interferon (IFN-I) productions in
CC plasmacytoid dendritic cells (pDCs). Independently of its transporter
CC activity, also promotes the recruitment of innate immune adapter TASL
CC to endolysosome downstream of TLR7, TLR8 and TLR9: TASL recruitment
CC leads to the specific recruitment and activation of IRF5 (By
CC similarity). Required for isotype class switch recombination to IgG2c
CC isotype in response to TLR9 stimulation. Required for mast cell
CC secretory-granule homeostasis by limiting mast cell functions and
CC inflammatory responses (By similarity). {ECO:0000250|UniProtKB:Q8N697,
CC ECO:0000250|UniProtKB:Q91W98, ECO:0000269|PubMed:9092568}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(out) + L-histidine(out) = H(+)(in) + L-histidine(in);
CC Xref=Rhea:RHEA:37047, ChEBI:CHEBI:15378, ChEBI:CHEBI:57595;
CC Evidence={ECO:0000269|PubMed:9092568};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:37048;
CC Evidence={ECO:0000305|PubMed:9092568};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a dipeptide(out) + H(+)(out) = a dipeptide(in) + H(+)(in);
CC Xref=Rhea:RHEA:64392, ChEBI:CHEBI:15378, ChEBI:CHEBI:90799;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64393;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an L-amino acid tripeptide(out) + H(+)(out) = an L-amino acid
CC tripeptide(in) + H(+)(in); Xref=Rhea:RHEA:64400, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:155837; Evidence={ECO:0000250|UniProtKB:Q8N697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64401;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(out) + N-acetylmuramyl-L-alanyl-D-isoglutamine(out) =
CC H(+)(in) + N-acetylmuramyl-L-alanyl-D-isoglutamine(in);
CC Xref=Rhea:RHEA:64408, ChEBI:CHEBI:15378, ChEBI:CHEBI:155830;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64409;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(out) + L-alanyl-gamma-D-glutamyl-meso-
CC diaminoheptanedioate(out) = H(+)(in) + L-alanyl-gamma-D-glutamyl-
CC meso-diaminoheptanedioate(in); Xref=Rhea:RHEA:64412,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:61401;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64413;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=glycyl-sarcosine(out) + H(+)(out) = glycyl-sarcosine(in) +
CC H(+)(in); Xref=Rhea:RHEA:64396, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:155838; Evidence={ECO:0000250|UniProtKB:Q8N697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64397;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=carnosine(out) + H(+)(out) = carnosine(in) + H(+)(in);
CC Xref=Rhea:RHEA:64404, ChEBI:CHEBI:15378, ChEBI:CHEBI:57485;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64405;
CC Evidence={ECO:0000250|UniProtKB:Q8N697};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=17 uM for histidine (at pH 5.5) {ECO:0000269|PubMed:9092568};
CC -!- SUBUNIT: Interacts with TASL; leading to TASL recruitment to
CC endolysosome. {ECO:0000250|UniProtKB:Q8N697}.
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:Q8N697};
CC Multi-pass membrane protein {ECO:0000255}. Endosome membrane
CC {ECO:0000250|UniProtKB:Q8N697}; Multi-pass membrane protein
CC {ECO:0000255}. Early endosome membrane {ECO:0000250|UniProtKB:Q91W98};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Widely expressed in the gastrointestinal tract.
CC Highly expressed in the brain and eye, and weakly in the lung and
CC spleen. In brain highly expressed in the hippocampus, cerebellum and
CC pontine nucleus, and weakly in other regions of the brain, including
CC the cerebral cortex, brain stem, thalamus and hypothalamus.
CC {ECO:0000269|PubMed:11741260, ECO:0000269|PubMed:9092568}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. Proton-
CC dependent oligopeptide transporter (POT/PTR) (TC 2.A.17) family.
CC {ECO:0000305}.
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DR EMBL; AB000280; BAA20489.1; -; mRNA.
DR EMBL; BC087709; AAH87709.1; -; mRNA.
DR RefSeq; NP_653359.1; NM_144758.1.
DR AlphaFoldDB; O09014; -.
DR SMR; O09014; -.
DR STRING; 10116.ENSRNOP00000001277; -.
DR jPOST; O09014; -.
DR PaxDb; O09014; -.
DR PRIDE; O09014; -.
DR GeneID; 246280; -.
DR KEGG; rno:246280; -.
DR UCSC; RGD:708469; rat.
DR CTD; 121260; -.
DR RGD; 708469; Slc15a4.
DR eggNOG; KOG1237; Eukaryota.
DR InParanoid; O09014; -.
DR OrthoDB; 365203at2759; -.
DR PhylomeDB; O09014; -.
DR TreeFam; TF330897; -.
DR Reactome; R-RNO-427975; Proton/oligopeptide cotransporters.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:O09014; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0031901; C:early endosome membrane; ISO:RGD.
DR GO; GO:0036020; C:endolysosome membrane; ISS:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; ISO:RGD.
DR GO; GO:0031303; C:integral component of endosome membrane; ISO:RGD.
DR GO; GO:1905103; C:integral component of lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; ISO:RGD.
DR GO; GO:0071916; F:dipeptide transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005290; F:L-histidine transmembrane transporter activity; IMP:RGD.
DR GO; GO:0015333; F:peptide:proton symporter activity; ISS:UniProtKB.
DR GO; GO:0015647; F:peptidoglycan transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0140206; P:dipeptide import across plasma membrane; ISS:UniProtKB.
DR GO; GO:0015817; P:histidine transport; IMP:RGD.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0089708; P:L-histidine transmembrane export from vacuole; ISO:RGD.
DR GO; GO:0033023; P:mast cell homeostasis; ISS:UniProtKB.
DR GO; GO:0015835; P:peptidoglycan transport; ISS:UniProtKB.
DR GO; GO:0045089; P:positive regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:0070430; P:positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; ISS:UniProtKB.
DR GO; GO:0070434; P:positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; ISS:UniProtKB.
DR GO; GO:0034157; P:positive regulation of toll-like receptor 7 signaling pathway; ISS:UniProtKB.
DR GO; GO:0034161; P:positive regulation of toll-like receptor 8 signaling pathway; ISS:UniProtKB.
DR GO; GO:0034165; P:positive regulation of toll-like receptor 9 signaling pathway; ISS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0048302; P:regulation of isotype switching to IgG isotypes; ISS:UniProtKB.
DR GO; GO:0070424; P:regulation of nucleotide-binding oligomerization domain containing signaling pathway; ISS:UniProtKB.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR036259; MFS_trans_sf.
DR InterPro; IPR000109; POT_fam.
DR InterPro; IPR018456; PTR2_symporter_CS.
DR PANTHER; PTHR11654; PTHR11654; 1.
DR Pfam; PF00854; PTR2; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
DR PROSITE; PS01023; PTR2_2; 1.
PE 1: Evidence at protein level;
KW Endosome; Immunity; Innate immunity; Lysosome; Membrane; Peptide transport;
KW Phosphoprotein; Protein transport; Reference proteome; Symport;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..572
FT /note="Solute carrier family 15 member 4"
FT /id="PRO_0000338601"
FT TRANSMEM 40..60
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 67..87
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 96..116
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 159..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 195..215
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 223..243
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 317..337
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 362..382
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 404..424
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 458..478
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 489..509
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 534..554
FT /note="Helical"
FT /evidence="ECO:0000255"
FT MOD_RES 279
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91W98"
FT MOD_RES 297
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N697"
FT CONFLICT 302
FT /note="R -> H (in Ref. 2; AAH87709)"
FT /evidence="ECO:0000305"
FT CONFLICT 307
FT /note="T -> I (in Ref. 2; AAH87709)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 572 AA; 61949 MW; 8471EE4967E2987B CRC64;
MEGERAPLLG SRRAAAAAGV FAGRRAACGA VLLAELLERA AFYGVTANLV LFLNGAPFNW
EGAQASQALL LFMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPRSR
SFLCGDPHPE LVRNCSAPFP NGTAVCPDAA ARRCAPATFA GLVLVGLGVA TVKANITPFG
ADQVKDRGPE ATRRFFNWFY WSINLGAILS LGGIAYIQQN VSFLTGYLIP TVCVAIAFLV
FLCGQSVFIT KPPDGSAFTD MFRILTYSCC SQRGGQRRSG EGLGVFQQSS KHSLFDSCKM
SRGGPFTEDK VEDVKALVKI VPVFLALIPY WTVYFQMQTT YVLQSLHLKI PEISSITTTH
HTLPAAWLTM FDAVLILLLI PLKDKLVDPV LRRHGLLPSS LKRIAVGMFF VTCSAFAAGI
LESKRLDLVK EKTINQTIGG VVYHAADLPI WWQIPQYVLI GISEIFASIA GLEFAYSAAP
KSMQSAIMGL FFFFSGIGSF VGSGLLALVS LKAIGWMSSH TDFGNINSCH LHYYFFLLAA
IQGATLLLFL IVSVKYDRQR ARTDGGTAST RT
