Cloning and characterization of the gene encoding the mouse peptide transporter PEPT2.

A002590

doi:10.1038/mp.a002590.01

Pept1

Slc15a1

intestinal peptide transporter PEPT1

Pect1

Pept1

PET1

Slc15a1

Solute carrier family 15 (oligopeptide transporter), member 1

Solute carrier family 15 member 1

Transporter, facilitator

2006-07-26

Wolfgang Sadee

sadee-1@medctr.osu.edu

Pharmacology, Ohio State University, OH 43210-1239, US

Wolfgang Sadee

Pharmacology, Ohio State University, OH 43210-1239, US

Pascale Anderle

Laboratory of Experimental Cancer Research, Istituto Oncologico della Svizzera Italiana, Bellinzona 1066, CH

Paul A Dawson

pdawson@wfubmc.edu

Mouse

16716359

NP_444309.1

MGMSKSRGCFGYPLSIFFIVVNEFCERFSYYGMRALLVLYFRNFLGWDDNLSTAIYHTFVALCYLTPILGALIADSWLGKFKTIVSLSIVYTIGQAVISVSSINDLTDHDHNGSPDSLPVHVALSMVGLALIALGTGGIKPCVSAFGGDQFEEGQEKQRNRFFSIFYLAINGGSLLSTIITPILRVQQCGIHSQQACYPLAFGVPAALMAVALIVFVLGSGMYKKFQPQGNIMGKVAKCIGFAIKNRFRHRSKAYPKREHWLDWAKEKYDERLISQIKMVTKVMFLFIPLPMFWGLFDQQGSRWTLQATTMNGKIGANEIQPDQMQTVNAILNVNNGPNVDAVVYRSIAKCGFNFTSLKKMTVGMFLASMAFVVAAIVQVEIDKTLPVFPGGNQVQIKVLNIGNNNMTVHFPGNSVTLAQMSQTDTFMTFDIDKLTSINISSSGSPGVTTVAHDFEQGHRHNLLVWEPSQYRVVKDGPNQKPEKGENGIRFVNTLNEMVTNKMSGKVYEKFTSHNASGYKFLPSGEKQYTINTTAVAPTCLTDFKSSNLDFGSAYTYVIRRASDGCLEVKEFEDIPPNTVNMALQIPQYFLLTCGEVVFSVTGLEFSYSQAPSNMKSVLQAGWLLTVAVGNIIVLIVAGAGHFPKQWAEYILFASLLLVVCVIFAIMARFYTYINPAEIEAQFDEDEKKKGIGKENPYSSLEPVSQTNM

PEPT1, also called SLC15A1, belongs to the SLC15 family (solute carrier proteins). The SLC series comprises genes encoding passive transporters, ion-coupled secondary active transporters, and exchangers. A transporter is assigned to a specific SLC family if it has at least 20–25% sequence amino-acid similarity to other members of that family. The SLC15 family comprises four members, namely SLC15A1 (PEPT1), SLC15A2 (PEPT2), SLC15A3 (PHT2, PTR3), and SLC15A4 (PHT1, PTR4). These four members of the SLC15 family belong to the proton-dependent oligopeptide transporter (POT) family. The POT proteins function as symporters with protons, which provide the driving force for transport across the plasma membrane. The four mammalian proteins are known to transport dipeptides, whereas the transport of tripeptides has been shown only for PEPT1 and PEPT2. Both PEPT1 and PEPT2 are thought to be capable of transporting the 400 dipeptides and 8,000 tripeptides that are derived from the 20 natural L-amino acids, the main source for food-derived proteins. Moreover, both proteins transport ω-amino fatty acids carrying a positively and a negatively charged headgroup separated by at least four methylene groups. Beside their role in active absorption of food-derived dipeptides and tripeptides, both transporters are known to transport a large number of bioactive, structurally related compounds such as various cephalosporins, angiotensin-converting enzyme inhibitors, and 5′-amino acid esters of the antiviral nucleosides, acyclovir and zidovudine (AZT).

PEPT1, also called SLC15A1 according to the official Human Genome Organization (HUGO) system nomenclature, belongs to the SLC15 family (solute carrier proteins). The solute carrier family includes 43 families and 298 transporter genes in humans. The SLC series comprises genes encoding passive transporters, ion-coupled secondary active transporters, and exchangers. A transporter is assigned to a specific SLC family if it has at least 20–25% sequence amino-acid similarity to other members of that family (Hediger et al. 2004). The SLC15 family comprises four members, namely SLC15A1 (PEPT1), SLC15A2 (PEPT2), SLC15A3 (PHT2, PTR3), and SLC15A4 (PHT1, PTR4). These four members of the SLC15 family belong to the proton-dependent oligopeptide transporter (POT) family according to the official <a href="http://www.tcdb.org/">transporter classification system</a>. Mammalian orthologs of human SLC15A1 (Liang et al. 1995) have been identified for rat (Saito et al. 1995), mouse (Fei et al. 2000), pig (NM_214347; Klang et al. 2005), dog (NM_001003036; Etienne, N.M.D., Matthews, A.D., Matthews, J.C. and Davenport, G.M., unpublished observations), and recently monkey (Zhang et al. 2004), whereas the orthologs of human SLC15A2 (Liu et al. 1995) are known for mouse (Rubio-Aliaga et al. 2000) and rat (Saito et al. 1996). Orthologs of human SLC15A3 (Sakata et al. 2001) and SLC15A4 (Botka et al. 2000) are available for mouse only (Takahashi et al. 2000, Okazaki et al. 2002). Rabbit Pept1 was first cloned in 1994 (Fei et al. 1994), and the human ortholog was cloned shortly thereafter (Liang et al. 1995). The POT proteins function as symporters with protons, which provide the driving force for transport across the plasma membrane. The four mammalian proteins are known to transport dipeptides, whereas the transport of tripeptides has been shown only for PEPT1 and PEPT2. In addition, PTR3 and PTR4 transport histidine (Daniel and Kottra 2004). The human SLC15 proteins are 577–729 amino-acid residues in length (SLC15A1, 708 residues; SLC15A2, 729 residues; SLC15A3, 581 residues; SLC15A4, 577 residues), with the eukaryotic proteins in general being longer than the corresponding bacterial proteins. Hydropathy analysis indicates a secondary structure consisting of 12 transmembrane α-helical spanners. Studies on the topology of human PEPT1 (hPEPT1) are consistent with this prediction (Covitz et al. 1998). Some members of the POT family exhibit limited sequence similarity to protein members of the major facilitator superfamily (MFS). Thus, the POT family is classified as a family within the MFS. Both PEPT1 and PEPT2 are thought to be capable of transporting the 400 dipeptides and 8,000 tripeptides that are derived from the 20 natural L-amino acids, the main source for food-derived proteins (Daniel and Kottra 2004). Moreover, both proteins transport ω-amino fatty acids carrying a positively and a negatively charged headgroup separated by at least four methylene groups (Döring et al. 1998). Beside their role in active absorption of food-derived dipeptides and tripeptides, both transporters are known to transport a large number of bioactive, structurally related compounds such as various cephalosporins, angiotensin-converting enzyme inhibitors, and 5′-amino acid esters of the antiviral nucleosides, acyclovir and zidovudine (AZT) (Ganapathy et al. 1995, Han et al. 1998).

TATA boxes exist 520 base pairs (bp) upstream of the transcription start site in human SLC15A1 (Urtti et al. 2001). The putative regulatory region also contains GC boxes; thus, several GC boxes are located within 300 bp of the transcription site in SLC15A1. Binding sites for transcription factors do not include any amino-acid-responsive element; however, some transcription factor binding sites for insulin response were observed (Urtti et al. 2001). Recently, the promoter activity of SLC15A1 has been characterized and it was shown that Sp1 functions as a basal transcriptional regulator for the gene encoding SLC15A1 (Shimakura et al. 2005). The proximal promoter region of the rat Pept1 gene has a TATA-like box and a GC box sequence. The luciferase activities of the clone −351 RPT-LUC responded to some amino acids (phenylalanine, arginine, and lysine) and dipeptides (Gly-Sar, Gly-Phe, Lys-Phe, and Asp-Lys). An AP-1-binding site and an amino-acid-responsive element are present at −295 and −277 nucleotides, respectively, relative to the transcription start site in this region. These results suggest that the upregulation of dipeptide transport activity by dietary protein is caused by transcriptional activation of the PepT1 gene by selective amino acids and dipeptides in the diet (Shiraga et al. 1999). In mice, the transcription start site lies 31 bp upstream of the translation start site. The promoter region upstream of the transcription start site does not contain the TATA box but possesses three GC boxes, which constitute a binding site for the transcription activator SP1 (Fei et al. 2000).

PEPT1 selectively transports dipeptides and tripeptides, whereas longer peptides are poor substrates. However, a variety of other structures also serve as substrates. The most basic structures known to interact with Pept1 are ω-amino fatty acids possessing a negatively and a positively charged headgroup separated by four methylene groups (Döring et al. 1998). Additional features affect substrate affinity (Bailey et al. 2000). Substrates with known pharmacological effects that interact with Pept1 are various amino-β-lactam antibiotics (different cephalosporins and penicillin derivatives), angiotensin-converting enzyme inhibitors, nucleoside-type antiviral drugs (5′-amino-acid esters of the antiviral nucleosides, acyclovir and AZT), L-DOPA derivatives, sulpiride, and bestatin (Ganapathy et al. 1995, Saito et al. 1996, Han et al. 1998, Tamai et al. 1998, Watanabe et al. 2002). To our knowledge, no endogenous protein is known to interact directly with Pept1. PEPT1-mediated transport of peptides and peptoid drugs depends on an H+ gradient, which is maintained at the plasma membrane mainly by Na+/H+ exchangers (Kennedy et al. 2002). It remains to be documented whether PEPT1 is in physical proximity to an Na+/H+ exchanger. Phosphorylation has been shown to regulate PEPT1 activity. Kinetic analysis in Caco-2 cells showed that the protein kinase C (PKC)-induced inhibition is associated with a decrease in the maximal velocity of the transport system with no change in the affinity of the system for its substrates (Brandsch et al. 1994). Various putative phosphorylation sites for protein kinases have been described for the Pept1 protein. Whereas rabbit Pept1 has only one putative PKC phosphorylation site and one putative cAMP-dependent protein kinase (PKA) phosphorylation site (Fei et al. 1994), hPEPT1 has two putative PKC phosphorylation sites but no putative site for PKA phosphorylation (Liang et al. 1995). Rat Pept1 has one putative PKC phosphorylation site and one putative PKA phosphorylation site (Miyamoto et al. 1996).

Various factors contribute to the regulation of PEPT1 expression in the brush border membrane (Adibi 2003). Studies in Caco-2 cells have shown that PEPT1 expression is upregulated by natural and chemically synthesized dipeptides (Thamotharan et al. 1998, Adibi 2003). The expression of messenger RNA and protein is upregulated, possibly as a result of stabilization of RNA and an increase in mRNA transcription (Walker et al. 1998). In vivo studies in rats have revealed that a high-protein meal increases the gene expression of Slc15a1, leading to increased protein expression in the brush border membrane (Shiraga et al. 1999). Brief or prolonged fasting of rats also results in an increase in Pept1 transporter population. However, the underlying mechanisms are unknown (Thamotharan et al. 1999, Ihara et al. 2000). The effect of various hormones on Pept1 expression in the brush border membrane has been examined. Effects of leptin and insulin on the protein expression in the brush border membrane seem to result from the translocation of Pept1 from an intracellular pool to the membrane. In contrast, the mechanism by which epidermal growth factor increases dipeptide transport in a dose-dependent manner remains unknown (Thamotharan et al. 1999, Buyse et al. 2001, Nielsen et al. 2003). Whereas the signaling of α2-adrenergic receptors through clonidine seems to increase the translocation of preformed cytoplasmic Pept1 to the apical membrane of Caco-2 cells, the signaling of σ receptors through pentazocine increases the level of PEPT1 mRNA in Caco-2 cells (Fujita et al. 1999, Berlioz et al. 2000). 5-Fluorouracil has been suggested to increase the synthesis of rat Pept1 (Tanaka et al. 1998).

The expression of rat Pept1 in the small intestine is restricted to the brush border of the differentiated absorptive epithelial cells, as shown by immunohistochemistry (Ogihara et al. 1996). Similarly, in humans PEPT1 expression is high in the apical region of duodenal, jejunal, and ileal villus epithelial cells, but low in absorptive colonocytes (Ziegler et al. 2002). Immunoreactive hPEPT1 is expressed at lower levels in the colon than in the ileum. Whereas the expression in the ileum was shown to be localized to the apical enterocyte membrane along the length of the crypt–villus axis, expression in the colonocyte was detectable at the apical membrane toward the luminal surface but was predominant at the basal membrane toward the base of the crypt (Ford et al. 2003). The use of western blot analysis of lysosomal membrane proteins with anti-PEPT1 antibody revealed the presence of an immunoreactive protein (Zhou et al. 2000).

Rabbit Pept1 mRNA was found in intestine, kidney, and liver, and in small amounts in brain (Fei et al. 1994). Northern blot analysis detected rat Pept1 mRNA in the small intestine and kidney (Saito et al. 1995, Miyamoto et al. 1996), whereas real-time polymerase chain reaction analysis of the gastro-intestinal tract revealed, in addition, PEPT1 expression in the stomach and large intestine (Herrera-Ruiz et al. 2001). Expression of PEPT1 mRNA in human tissues was shown in the small intestine, placenta, liver, kidney, and pancreas (Liang et al. 1995). Moreover, hPEPT1 is upregulated in the colon of patients with ulcerative colitis and Crohn’s disease, and is highly expressed in pancreatic cancer cells (Gonzalez et al. 1998, Merlin et al. 2001).

In humans, no disease state has yet been linked to genetic variations of the gene encoding SLC15A1. Zhang et al. (2004) identified four synonymous and nine non-synonymous genetic variations of SLC15A1. All non-synonymous PEPT1 variants have conserved substrate recognition and transport functions. However, one rare variant (P586L) displayed a profound decrease in uptake capacity.

Saito et al. (1997) have isolated from a human duodenal library a cDNA encoding a pH-sensing regulatory factor protein (hPEPT1-RF) that modulates the transport activity of PEPT1. Amino-acid residues 18–195 of hPEPT1-RF are identical to residues 8–185 of hPEPT1, whereas residues 1–17 and 196–208 are unique. hPEPT1-RF showed no transport activity of glycylsarcosine but shifted the pH profile of dipeptide transport mediated by the coexpressed hPEPT1. Urtti et al. (2001) indicated that hPEPT1 and hPEPT1-RF are splice variants encoded by the same gene, consisting of 24 exons, located in chromosome 13. hPEPT1 is encoded by 23 exons and hPEPT1-RF by 6 exons. Coding sequences of hPEPT1-RF share three exons completely and two exons partly with hPEPT1.

The following antibodies against rat, human, and rabbit Pept1 have been described in the literature and/or are commercially available. 1. Rat polyclonal antisera raised in rabbits directed against the C-terminal amino acids of the rat PepT1 protein (ENPYSSLEPVSQTNM and an additional cysteine residue at the N terminus, and linked to keyhole limpet hemocyanin (KLH) with m-maleimidobenzoyl-N-hydroxysuccinimide ester) (Saito et al. 1995). 2. Rat polyclonal antisera directed against a synthetic 12-amino acid peptide corresponding to the C-terminal region of rat PepT1 (YSSLEPVSQTNM, amino acids 699–710). An N-terminal cysteine residue was added to the peptide to facilitate coupling of the peptide to the carrier protein, KLH (Shen et al. 1999). 3. Rat anti-Pept1 polyclonal antibody raised in rabbits against two synthetic peptides (PGHRHTLLVWGPNLY and QKPEKGENGIRFVST) (Yang et al. 2002). 4. Polyclonal antiserum was raised in rabbits against 15 amino acids of the C terminus of hPEPT1 (KSNPYFMSGANSQKQ). One cysteine residue was added to the N terminus to allow oligopeptide coupling to the carrier protein, KLH (Covitz et al. 1998). 5. Anti-P085 antibody was raised in rabbit against a synthetic peptide (RLEKSNPYFMSGANS) corresponding to residues 690–704 of the cytoplasmic terminal domain of hPEPT1 (Walker et al. 1998). 6. Human anti-PEPT1 polyclonal antibody was raised in mice against two synthetic peptides (CDGLTQKSDKGENGIR and KEQCRRDFESPYL) (Basu et al. 1998). 7. Affinity-purified anti-hPEPT1 was raised in rabbits against a synthetic peptide (CTMSGKIGALEI) (Rockland Immunochemicals, Inc., Gilbertsville, Pennsylvania, USA). 8. Polyclonal antibody was affinity-purified from whole rabbit serum prepared by repeated immunizations with a synthetic peptide (CTMSGKIGALEI) corresponding to hPEPT1 conjugated to carrier protein. A cysteine residue was added to the C-terminal end to facilitate coupling. Reactivity is observed against hPEPT1; cross-reactivity with Pept1 from other mammalian sources has not been tested (Biotrend, Köln, Germany). 9. Rabbit polyclonal antibody raised against a recombinant protein corresponding to amino acids 366–600 mapping near the C terminus of PEPT1 of human origin (Santa Cruz Biotechnology, Inc., Santa Cruz, California, USA). 10. Rabbit anti-Pept1 polyclonal antibody was raised against a synthetic peptide (CYPSLAPVSQTQM) corresponding to the deduced C-terminal amino acid sequence of Pept1 (Sai et al. 1996).

(Slc15a1)[2]

Pept1

plasma membrane

GO:0005886

Pept1

Slc15a1

A002590

Interactions of Pept1 (Slc15a1) with other proteins have yet to be demonstrated experimentally.

8139693

(Slc15a1)[2]

alanyl-alanine

Yes

63.0 µM

14706811

(Slc15a1)[2]

Glycyl-sarcosine

Yes

600.0 µM

Yes Glycyl-sarcosine is used as a common substrate for Slc15a1/Pept1.

12397398

SLC15A[1-4]

Transporters, SLC15_A002590

SLC15A4

SLC15A2

SLC15A1

SLC15A3

This peptide transporter family differs in primary sequence from most other transporter families; only low-level sequence similarity to a few other solute transporters has been observed.

9144720

11027540

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9458100

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9523324

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8769308

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19 Aug 1996

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May 1999

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Apr 1997

java.util.NoSuchElementException
	at java.util.HashMap$HashIterator.nextEntry(HashMap.java:785)
	at java.util.HashMap$KeyIterator.next(HashMap.java:818)
	at java.util.AbstractCollection.toArray(AbstractCollection.java:174)
	at java.util.ArrayList.<init>(ArrayList.java:136)
	at org.cellularsignaling.servlets.filters.HostThrottlingFilter$HostThrottlingInfo.sweep(HostThrottlingFilter.java:259)
	at org.cellularsignaling.servlets.filters.HostThrottlingFilter$HostThrottlingInfo.sweepIfNecessary(HostThrottlingFilter.java:245)
	at org.cellularsignaling.servlets.filters.HostThrottlingFilter$HostThrottlingInfo.access$200(HostThrottlingFilter.java:232)
	at org.cellularsignaling.servlets.filters.HostThrottlingFilter.doFilter(HostThrottlingFilter.java:215)
	at com.evermind[Oracle Application Server Containers for J2EE 10g (9.0.4.0.0)].server.http.ServletRequestDispatcher.invoke(ServletRequestDispatcher.java:604)
	at com.evermind[Oracle Application Server Containers for J2EE 10g (9.0.4.0.0)].server.http.ServletRequestDispatcher.forwardInternal(ServletRequestDispatcher.java:317)
	at com.evermind[Oracle Application Server Containers for J2EE 10g (9.0.4.0.0)].server.http.HttpRequestHandler.processRequest(HttpRequestHandler.java:790)
	at com.evermind[Oracle Application Server Containers for J2EE 10g (9.0.4.0.0)].server.http.HttpRequestHandler.run(HttpRequestHandler.java:270)
	at com.evermind[Oracle Application Server Containers for J2EE 10g (9.0.4.0.0)].server.http.HttpRequestHandler.run(HttpRequestHandler.java:112)
	at com.evermind[Oracle Application Server Containers for J2EE 10g (9.0.4.0.0)].util.ReleasableResourcePooledExecutor$MyWorker.run(ReleasableResourcePooledExecutor.java:192)
	at java.lang.Thread.run(Thread.java:534)