UniProtKB - Q8N697 (S15A4_HUMAN)
Protein
Solute carrier family 15 member 4
Gene
SLC15A4
Organism
Homo sapiens (Human)
Status
Functioni
Proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune response (PubMed:16289537, PubMed:25238095, PubMed:29224352). Able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans (PubMed:29224352, PubMed:31073693). Transporter activity is pH-dependent and maximized in the acidic lysosomal environment (By similarity). Involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycans across the endolysosomal membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (PubMed:25238095, PubMed:29224352). Required for TLR7, TLR8 and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) (PubMed:25238095). Independently of its transporter activity, also promotes the recruitment of innate immune adapter TASL to endolysosome downstream of TLR7, TLR8 and TLR9: TASL recruitment leads to the specific recruitment and activation of IRF5 (PubMed:32433612). Required for isotype class switch recombination to IgG2c isotype in response to TLR9 stimulation (By similarity). Required for mast cell secretory-granule homeostasis by limiting mast cell functions and inflammatory responses (By similarity).By similarity5 Publications
Catalytic activityi
- This reaction proceeds in the forward2 Publications direction.
- This reaction proceeds in the forward1 Publication direction.
- This reaction proceeds in the forward1 Publication direction.
- H+(out) + N-acetylmuramyl-L-alanyl-D-isoglutamine(out) = H+(in) + N-acetylmuramyl-L-alanyl-D-isoglutamine(in)1 PublicationThis reaction proceeds in the forward1 Publication direction.
- H+(out) + L-alanyl-γ-D-glutamyl-meso-diaminoheptanedioate(out) = H+(in) + L-alanyl-γ-D-glutamyl-meso-diaminoheptanedioate(in)2 PublicationsThis reaction proceeds in the forward2 Publications direction.
- This reaction proceeds in the forward1 Publication direction.
- This reaction proceeds in the forward1 Publication direction.
Kineticsi
- KM=16.3 µM for L-histidine1 Publication
- KM=1690 µM for GlySar dipeptide1 Publication
- Vmax=1317 pmol/min/mg enzyme with L-histidine as substrate1 Publication
- Vmax=100 pmol/min/mg enzyme with GlySar dipeptide as substrate1 Publication
GO - Molecular functioni
- dipeptide transmembrane transporter activity Source: UniProtKB
- L-histidine transmembrane transporter activity Source: UniProtKB
- peptide:proton symporter activity Source: UniProtKB
- peptidoglycan transmembrane transporter activity Source: UniProtKB
GO - Biological processi
- dipeptide import across plasma membrane Source: UniProtKB
- histidine transport Source: GO_Central
- innate immune response Source: UniProtKB-KW
- ion transport Source: Reactome
- L-histidine transmembrane export from vacuole Source: Ensembl
- mast cell homeostasis Source: UniProtKB
- neutrophil degranulation Source: Reactome
- peptidoglycan transport Source: UniProtKB
- positive regulation of innate immune response Source: UniProtKB
- positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway Source: UniProtKB
- positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway Source: UniProtKB
- positive regulation of toll-like receptor 7 signaling pathway Source: UniProtKB
- positive regulation of toll-like receptor 8 signaling pathway Source: UniProtKB
- positive regulation of toll-like receptor 9 signaling pathway Source: UniProtKB
- protein transport Source: UniProtKB-KW
- regulation of isotype switching to IgG isotypes Source: UniProtKB
- regulation of nucleotide-binding oligomerization domain containing signaling pathway Source: UniProtKB
Keywordsi
Biological process | Immunity, Innate immunity, Peptide transport, Protein transport, Symport, Transport |
Enzyme and pathway databases
PathwayCommonsi | Q8N697 |
Reactomei | R-HSA-427975, Proton/oligopeptide cotransporters R-HSA-6798695, Neutrophil degranulation |
Protein family/group databases
TCDBi | 2.A.17.3.11, the proton-dependent oligopeptide transporter (pot/ptr) family |
Names & Taxonomyi
Protein namesi | Recommended name: Solute carrier family 15 member 4CuratedAlternative name(s): Peptide transporter 41 Publication Peptide/histidine transporter 12 Publications Short name: hPHT12 Publications |
Gene namesi | ORF Names:FP12591 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:23090, SLC15A4 |
MIMi | 615806, gene |
neXtProti | NX_Q8N697 |
VEuPathDBi | HostDB:ENSG00000139370.10 |
Subcellular locationi
Lysosome
- Lysosome membrane 3 Publications; Multi-pass membrane protein Sequence analysis
Endosome
- Endosome membrane 1 Publication; Multi-pass membrane protein Sequence analysis
- Early endosome membrane By similarity; Multi-pass membrane protein Sequence analysis
Endosome
- early endosome membrane Source: UniProtKB-SubCell
- endolysosome membrane Source: UniProtKB
- integral component of endosome membrane Source: Ensembl
Lysosome
- endolysosome membrane Source: UniProtKB
- integral component of lysosomal membrane Source: UniProtKB
- lysosomal membrane Source: Reactome
Plasma Membrane
- plasma membrane Source: Reactome
Other locations
- specific granule membrane Source: Reactome
Topology
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Transmembranei | 49 – 69 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 76 – 96 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 105 – 125 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 158 – 178 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 194 – 214 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 222 – 242 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 318 – 338 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 363 – 383 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 405 – 425 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 459 – 479 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 490 – 510 | HelicalSequence analysisAdd BLAST | 21 | |
Transmembranei | 535 – 555 | HelicalSequence analysisAdd BLAST | 21 |
Keywords - Cellular componenti
Endosome, Lysosome, MembranePathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 14 – 15 | LL → AA: Abolished localization to the lysosome membrane and promotes relocalization to the plasma membrane; when associated with 318-A-A-319. Does not affect interaction with TASL. 2 Publications | 2 | |
Mutagenesisi | 44 | E → A: Does not affect interaction with TASL. 1 Publication | 1 | |
Mutagenesisi | 47 | E → A: Does not affect interaction with TASL. 1 Publication | 1 | |
Mutagenesisi | 318 – 319 | LV → AA: Abolished localization to the lysosome membrane and promotes relocalization to the plasma membrane; when associated with 14-A-A-15. 1 Publication | 2 | |
Mutagenesisi | 465 | E → K: Abolished transmembrane transporter activity. Abolished interaction with TASL. 2 Publications | 1 |
Organism-specific databases
DisGeNETi | 121260 |
OpenTargetsi | ENSG00000139370 |
PharmGKBi | PA134928948 |
Miscellaneous databases
Pharosi | Q8N697, Tbio |
Genetic variation databases
BioMutai | SLC15A4 |
DMDMi | 74751048 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000338599 | 1 – 577 | Solute carrier family 15 member 4Add BLAST | 577 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 279 | PhosphoserineBy similarity | 1 | |
Modified residuei | 298 | PhosphoserineCombined sources | 1 |
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | Q8N697 |
jPOSTi | Q8N697 |
MassIVEi | Q8N697 |
MaxQBi | Q8N697 |
PaxDbi | Q8N697 |
PeptideAtlasi | Q8N697 |
PRIDEi | Q8N697 |
ProteomicsDBi | 72148 [Q8N697-1] 72149 [Q8N697-2] |
PTM databases
GlyGeni | Q8N697, 1 site |
iPTMneti | Q8N697 |
PhosphoSitePlusi | Q8N697 |
SwissPalmi | Q8N697 |
Expressioni
Tissue specificityi
Highly expressed in skeletal muscle. Moderately expressed in kidney, liver, and heart. Weakly expressed in colon and brain. Expressed in low levels throughout the gastrointestinal tract and in Caco-2 cells. Expressed in retinal fragment epithelium (RPE) and neural retina. Expressed in small intestine, stomach, duodenum, jejunum, ileum and colon.3 Publications
Gene expression databases
Bgeei | ENSG00000139370, Expressed in blood and 221 other tissues |
ExpressionAtlasi | Q8N697, baseline and differential |
Genevisiblei | Q8N697, HS |
Organism-specific databases
HPAi | ENSG00000139370, Low tissue specificity |
Interactioni
Subunit structurei
Interacts with TASL; leading to TASL recruitment to endolysosome.
1 PublicationBinary interactionsi
Hide detailsProtein-protein interaction databases
BioGRIDi | 125714, 21 interactors |
DIPi | DIP-60839N |
IntActi | Q8N697, 17 interactors |
MINTi | Q8N697 |
STRINGi | 9606.ENSP00000266771 |
Miscellaneous databases
RNActi | Q8N697, protein |
Family & Domainsi
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 8 – 39 | Ala-richAdd BLAST | 32 |
Sequence similaritiesi
Belongs to the major facilitator superfamily. Proton-dependent oligopeptide transporter (POT/PTR) (TC 2.A.17) family. [View classification]Curated
Keywords - Domaini
Transmembrane, Transmembrane helixPhylogenomic databases
eggNOGi | KOG1237, Eukaryota |
GeneTreei | ENSGT00940000159361 |
HOGENOMi | CLU_009313_6_1_1 |
InParanoidi | Q8N697 |
OMAi | QMMGVWF |
OrthoDBi | 365203at2759 |
PhylomeDBi | Q8N697 |
TreeFami | TF330897 |
Family and domain databases
InterProi | View protein in InterPro IPR036259, MFS_trans_sf IPR000109, POT_fam IPR018456, PTR2_symporter_CS |
PANTHERi | PTHR11654, PTHR11654, 1 hit |
Pfami | View protein in Pfam PF00854, PTR2, 1 hit |
SUPFAMi | SSF103473, SSF103473, 1 hit |
PROSITEi | View protein in PROSITE PS01023, PTR2_2, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All
Isoform 1 (identifier: Q8N697-1) [UniParc]FASTAAdd to basket
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA
60 70 80 90 100
FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGSP FGGWLADARL
110 120 130 140 150
GRARAILLSL ALYLLGMLAF PLLAAPATRA ALCGSARLLN CTAPGPDAAA
160 170 180 190 200
RCCSPATFAG LVLVGLGVAT VKANITPFGA DQVKDRGPEA TRRFFNWFYW
210 220 230 240 250
SINLGAILSL GGIAYIQQNV SFVTGYAIPT VCVGLAFVVF LCGQSVFITK
260 270 280 290 300
PPDGSAFTDM FKILTYSCCS QKRSGERQSN GEGIGVFQQS SKQSLFDSCK
310 320 330 340 350
MSHGGPFTEE KVEDVKALVK IVPVFLALIP YWTVYFQMQT TYVLQSLHLR
360 370 380 390 400
IPEISNITTT PHTLPAAWLT MFDAVLILLL IPLKDKLVDP ILRRHGLLPS
410 420 430 440 450
SLKRIAVGMF FVMCSAFAAG ILESKRLNLV KEKTINQTIG NVVYHAADLS
460 470 480 490 500
LWWQVPQYLL IGISEIFASI AGLEFAYSAA PKSMQSAIMG LFFFFSGVGS
510 520 530 540 550
FVGSGLLALV SIKAIGWMSS HTDFGNINGC YLNYYFFLLA AIQGATLLLF
560 570
LIISVKYDHH RDHQRSRANG VPTSRRA
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketH7BYB7 | H7BYB7_HUMAN | Solute carrier family 15 member 4 | SLC15A4 | 238 | Annotation score: | ||
B6ZDF2 | B6ZDF2_HUMAN | Solute carrier family 15 member 4 | SLC15A4 | 155 | Annotation score: |
Sequence cautioni
The sequence AAI46804 differs from that shown. Reason: Frameshift.Curated
The sequence AAK95565 differs from that shown. Reason: Frameshift.Curated
The sequence AAQ04807 differs from that shown. Reason: Frameshift.Curated
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 24 | A → T in AAI46804 (PubMed:15489334).Curated | 1 | |
Sequence conflicti | 34 – 35 | RA → LL in AAK95565 (Ref. 1) Curated | 2 | |
Sequence conflicti | 44 | E → G in AAI46804 (PubMed:15489334).Curated | 1 |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_051611 | 239 | V → A. Corresponds to variant dbSNP:rs33990080Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_034052 | 1 – 337 | Missing in isoform 2. 2 PublicationsAdd BLAST | 337 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AY050629 mRNA Translation: AAK95565.1 Frameshift. AY038999 mRNA Translation: AAK72099.1 AF461893 mRNA Translation: AAQ04807.1 Frameshift. AK095717 mRNA Translation: BAG53113.1 CH471054 Genomic DNA Translation: EAW98494.1 BC028394 mRNA Translation: AAH28394.2 BC146803 mRNA Translation: AAI46804.1 Frameshift. |
CCDSi | CCDS9264.1 [Q8N697-1] |
RefSeqi | NP_663623.1, NM_145648.3 [Q8N697-1] |
Genome annotation databases
Ensembli | ENST00000266771; ENSP00000266771; ENSG00000139370 [Q8N697-1] |
GeneIDi | 121260 |
KEGGi | hsa:121260 |
UCSCi | uc001uhu.3, human [Q8N697-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AY050629 mRNA Translation: AAK95565.1 Frameshift. AY038999 mRNA Translation: AAK72099.1 AF461893 mRNA Translation: AAQ04807.1 Frameshift. AK095717 mRNA Translation: BAG53113.1 CH471054 Genomic DNA Translation: EAW98494.1 BC028394 mRNA Translation: AAH28394.2 BC146803 mRNA Translation: AAI46804.1 Frameshift. |
CCDSi | CCDS9264.1 [Q8N697-1] |
RefSeqi | NP_663623.1, NM_145648.3 [Q8N697-1] |
3D structure databases
ModBasei | Search... |
SWISS-MODEL-Workspacei | Submit a new modelling project... |
Protein-protein interaction databases
BioGRIDi | 125714, 21 interactors |
DIPi | DIP-60839N |
IntActi | Q8N697, 17 interactors |
MINTi | Q8N697 |
STRINGi | 9606.ENSP00000266771 |
Protein family/group databases
TCDBi | 2.A.17.3.11, the proton-dependent oligopeptide transporter (pot/ptr) family |
PTM databases
GlyGeni | Q8N697, 1 site |
iPTMneti | Q8N697 |
PhosphoSitePlusi | Q8N697 |
SwissPalmi | Q8N697 |
Genetic variation databases
BioMutai | SLC15A4 |
DMDMi | 74751048 |
Proteomic databases
EPDi | Q8N697 |
jPOSTi | Q8N697 |
MassIVEi | Q8N697 |
MaxQBi | Q8N697 |
PaxDbi | Q8N697 |
PeptideAtlasi | Q8N697 |
PRIDEi | Q8N697 |
ProteomicsDBi | 72148 [Q8N697-1] 72149 [Q8N697-2] |
Protocols and materials databases
Antibodypediai | 3084, 64 antibodies |
Genome annotation databases
Ensembli | ENST00000266771; ENSP00000266771; ENSG00000139370 [Q8N697-1] |
GeneIDi | 121260 |
KEGGi | hsa:121260 |
UCSCi | uc001uhu.3, human [Q8N697-1] |
Organism-specific databases
CTDi | 121260 |
DisGeNETi | 121260 |
GeneCardsi | SLC15A4 |
HGNCi | HGNC:23090, SLC15A4 |
HPAi | ENSG00000139370, Low tissue specificity |
MIMi | 615806, gene |
neXtProti | NX_Q8N697 |
OpenTargetsi | ENSG00000139370 |
PharmGKBi | PA134928948 |
VEuPathDBi | HostDB:ENSG00000139370.10 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG1237, Eukaryota |
GeneTreei | ENSGT00940000159361 |
HOGENOMi | CLU_009313_6_1_1 |
InParanoidi | Q8N697 |
OMAi | QMMGVWF |
OrthoDBi | 365203at2759 |
PhylomeDBi | Q8N697 |
TreeFami | TF330897 |
Enzyme and pathway databases
PathwayCommonsi | Q8N697 |
Reactomei | R-HSA-427975, Proton/oligopeptide cotransporters R-HSA-6798695, Neutrophil degranulation |
Miscellaneous databases
BioGRID-ORCSi | 121260, 6 hits in 879 CRISPR screens |
ChiTaRSi | SLC15A4, human |
GenomeRNAii | 121260 |
Pharosi | Q8N697, Tbio |
PROi | PR:Q8N697 |
RNActi | Q8N697, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000139370, Expressed in blood and 221 other tissues |
ExpressionAtlasi | Q8N697, baseline and differential |
Genevisiblei | Q8N697, HS |
Family and domain databases
InterProi | View protein in InterPro IPR036259, MFS_trans_sf IPR000109, POT_fam IPR018456, PTR2_symporter_CS |
PANTHERi | PTHR11654, PTHR11654, 1 hit |
Pfami | View protein in Pfam PF00854, PTR2, 1 hit |
SUPFAMi | SSF103473, SSF103473, 1 hit |
PROSITEi | View protein in PROSITE PS01023, PTR2_2, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | S15A4_HUMAN | |
Accessioni | Q8N697Primary (citable) accession number: Q8N697 Secondary accession number(s): A6H8Y9 Q8TAH0 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | June 10, 2008 |
Last sequence update: | October 1, 2002 | |
Last modified: | February 10, 2021 | |
This is version 139 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- Human chromosome 12
Human chromosome 12: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - SIMILARITY comments
Index of protein domains and families