P14740 (DPP4_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dipeptidyl peptidase 4
EC=3.4.14.5

Alternative name(s):
Bile canaliculus domain-specific membrane glycoprotein
Dipeptidyl peptidase IV
Short name=DPP IV
GP110 glycoprotein
T-cell activation antigen CD26
CD_antigen=CD26

Cleaved into the following 3 chains:

1. Dipeptidyl peptidase 4 membrane form
   Alternative name(s):
   Dipeptidyl peptidase IV membrane form
2. Dipeptidyl peptidase 4 soluble form
   Alternative name(s):
   Dipeptidyl peptidase IV soluble form
3. Dipeptidyl peptidase 4 60 kDa soluble form
   Alternative name(s):
   Dipeptidyl peptidase IV 60 kDa soluble form

Gene names

Name:	Dpp4
Synonyms:	Cd26

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	767 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones By similarity. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
Catalytic activity	Release of an N-terminal dipeptide, Xaa-Yaa-|-Zaa-, from a polypeptide, preferentially when Yaa is Pro, provided Zaa is neither Pro nor hydroxyproline.
Enzyme regulation	Inhibited by GPC3 and diprotin A By similarity.
Subunit structure	Monomer. Heterodimer with Seprase (FAP). Requires homodimerization for optimal dipeptidyl peptidase activity and T-cell costimulation. Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB. Associates with collagen. Interacts with PTPRC; the interaction is enhanced in a interleukin-12-dependent manner in activated lymphocytes. Interacts (extracellular domain) with ADA; does not inhibit its dipeptidyl peptidase activity. Interacts with CAV1 (via the N-terminus); the interaction is direct. Interacts (via cytoplasmic tail) with CARD11 (via PDZ domain); its homodimerization is necessary for interaction with CARD11. Interacts with IGF2R; the interaction is direct. Interacts with GPC3 By similarity. Homodimer.
Subcellular location	Dipeptidyl peptidase 4 soluble form: Secreted. Note: Detected in the serum and the seminal fluid By similarity. Cell membrane; Single-pass type II membrane protein. Apical cell membrane; Single-pass type II membrane protein By similarity. Cell projection › invadopodium membrane; Single-pass type II membrane protein By similarity. Cell projection › lamellipodium membrane; Single-pass type II membrane protein By similarity. Cell junction By similarity. Membrane raft By similarity. Note: Translocated to the apical membrane through the concerted action of N- and O-Glycans and its association with lipid microdomains containing cholesterol and sphingolipids. Redistributed to membrane rafts in T-cell in a interleukin-12-dependent activation. Its interaction with CAV1 is necessary for its translocation to membrane rafts. Colocalized with PTPRC in membrane rafts. Colocalized with FAP in invadopodia and lamellipodia of migratory activated endothelial cells in collagenous matrix. Colocalized with FAP on endothelial cells of capillary-like microvessels but not large vessels within invasive breast ductal carcinoma. Colocalized with ADA at the cell junction in lymphocyte-epithelial cell adhesion. Colocalized with IGF2R in internalized cytoplasmic vesicles adjacent to the cell surface By similarity.
Tissue specificity	Expressed in bile ducts and other epithelial brush borders (small intestine, kidney, colon, pancreatic duct); acinar structures in salivary glands; endothelial structures and T cell areas in thymus, spleen and lymph node. Ref.4
Post-translational modification	The soluble form (Dipeptidyl peptidase 4 soluble form also named SDPP) derives from the membrane form (Dipeptidyl peptidase 4 membrane form also named MDPP) by proteolytic processing By similarity. N- and O-Glycosylated By similarity. Ref.8 Phosphorylated. Mannose 6-phosphate residues in the carbohydrate moiety are necessary for interaction with IGF2R in activated T-cells. Mannose 6-phosphorylation is induced during T-cell activation By similarity.
Sequence similarities	Belongs to the peptidase S9B family. DPPIV subfamily.

Ontologies

Keywords
Biological process	Cell adhesion
Cellular component	Cell junction Cell membrane Cell projection Membrane Secreted
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Aminopeptidase Hydrolase Protease Serine protease
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	T cell costimulation Inferred from sequence or structural similarity. Source: UniProtKB cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW endothelial cell migration Inferred from sequence or structural similarity. Source: UniProtKB establishment of localization Inferred from mutant phenotype PubMed 15606609. Source: RGD negative regulation of extracellular matrix disassembly Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB proteolysis Inferred from direct assay PubMed 17415460. Source: RGD regulation of T cell mediated immunity Inferred from mutant phenotype PubMed 15606609. Source: RGD
Cellular_component	Golgi apparatus Inferred from direct assay PubMed 10931192. Source: RGD apical plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell cell junction Inferred from electronic annotation. Source: UniProtKB-SubCell cell surface Inferred from sequence or structural similarity. Source: UniProtKB endocytic vesicle Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum Inferred from direct assay PubMed 10931192. Source: RGD extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW invadopodium membrane Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium membrane Inferred from electronic annotation. Source: UniProtKB-SubCell membrane raft Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	aminopeptidase activity Inferred from electronic annotation. Source: UniProtKB-KW collagen binding Inferred from direct assay PubMed 8526932. Source: RGD dipeptidyl-peptidase activity Inferred from sequence or structural similarity. Source: UniProtKB peptide binding Inferred from direct assay PubMed 17415460. Source: RGD protease binding Inferred from sequence or structural similarity. Source: UniProtKB protein homodimerization activity Inferred from sequence or structural similarity. Source: UniProtKB receptor binding Inferred from sequence or structural similarity. Source: UniProtKB serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 767

767

Dipeptidyl peptidase 4 membrane form

PRO_0000027219

Chain

37 – 767

731

Dipeptidyl peptidase 4 soluble form

PRO_0000027220

Chain

281 – 767

487

Dipeptidyl peptidase 4 60 kDa soluble form

PRO_0000027221

Regions

Topological domain

1 – 6

6

Cytoplasmic Potential

Transmembrane

7 – 28

22

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

29 – 767

739

Extracellular Potential

Sites

Active site

631

1

Charge relay system By similarity

Active site

709

1

Charge relay system By similarity

Active site

741

1

Charge relay system By similarity

Amino acid modifications

Glycosylation

83

1

N-linked (GlcNAc...) Ref.8

Glycosylation

90

1

N-linked (GlcNAc...) Ref.8

Glycosylation

148

1

N-linked (GlcNAc...) By similarity

Glycosylation

217

1

N-linked (GlcNAc...) By similarity

Glycosylation

227

1

N-linked (GlcNAc...) Ref.8

Glycosylation

319

1

N-linked (GlcNAc...) Ref.8

Glycosylation

521

1

N-linked (GlcNAc...) Ref.8

Glycosylation

686

1

N-linked (GlcNAc...) By similarity

Disulfide bond

326 ↔ 337

Ref.8

Disulfide bond

383 ↔ 395

Ref.8

Disulfide bond

445 ↔ 448

Ref.8

Disulfide bond

455 ↔ 473

Ref.8

Disulfide bond

650 ↔ 763

Ref.8

Experimental info

Mutagenesis

629

1

G → A: Reduced activity. Ref.5

Mutagenesis

629

1

G → R: Reduced activity. Ref.5

Mutagenesis

630

1

W → E: No effect on activity. Ref.5

Mutagenesis

631

1

S → A: Reduced activity. Ref.5

Mutagenesis

632

1

Y → F: No effect on activity. Ref.5

Mutagenesis

632

1

Y → G: Reduced activity. Ref.5

Mutagenesis

632

1

Y → L: Reduced activity. Ref.5

Mutagenesis

633

1

G → A: Reduced activity. Ref.5

Mutagenesis

633

1

G → S: Reduced activity. Ref.5

Sequence conflict

38

1

R → A in AAA41096. Ref.1

Sequence conflict

54

1

Missing AA sequence Ref.4

Sequence conflict

183

1

I → T in AAA41272. Ref.2

Sequence conflict

332

1

T → N in AAA41272. Ref.2

Sequence conflict

352

1

C → V in AAA41272. Ref.2

Sequence conflict

394

1

V → D in AAA41272. Ref.2

Sequence conflict

562

1

L → F in AAA41272. Ref.2

Sequence conflict

624

1

R → Q in AAA41272. Ref.2

Secondary structure

1

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767

Helix Strand Turn

Details...

Helix

43 – 48

6

Beta strand

58 – 60

3

Beta strand

62 – 72

11

Beta strand

74 – 82

9

Beta strand

84 – 88

5

Helix

90 – 93

4

Helix

97 – 99

3

Beta strand

100 – 105

6

Beta strand

109 – 120

12

Beta strand

122 – 124

3

Beta strand

126 – 134

9

Turn

135 – 138

4

Beta strand

139 – 141

3

Beta strand

148 – 150

3

Beta strand

152 – 155

4

Beta strand

157 – 160

4

Beta strand

162 – 166

5

Beta strand

169 – 175

7

Turn

189 – 191

3

Beta strand

192 – 196

5

Helix

199 – 204

6

Beta strand

207 – 210

4

Beta strand

212 – 214

3

Beta strand

216 – 227

12

Beta strand

233 – 238

6

Beta strand

248 – 253

6

Beta strand

263 – 271

9

Helix

273 – 276

4

Beta strand

283 – 285

3

Turn

289 – 293

5

Beta strand

296 – 305

10

Beta strand

308 – 329

22

Turn

330 – 333

4

Beta strand

334 – 336

3

Helix

339 – 341

3

Beta strand

342 – 346

5

Beta strand

348 – 350

3

Beta strand

352 – 356

5

Beta strand

366 – 374

9

Beta strand

376 – 378

3

Beta strand

380 – 388

9

Turn

391 – 393

3

Beta strand

396 – 398

3

Beta strand

401 – 403

3

Beta strand

405 – 411

7

Beta strand

413 – 421

9

Helix

423 – 425

3

Beta strand

430 – 438

9

Beta strand

443 – 450

8

Turn

452 – 454

3

Beta strand

455 – 462

8

Beta strand

466 – 473

8

Beta strand

475 – 478

4

Beta strand

480 – 488

9

Beta strand

491 – 496

6

Helix

499 – 504

6

Helix

505 – 507

3

Beta strand

512 – 520

9

Beta strand

523 – 531

9

Beta strand

541 – 547

7

Helix

564 – 570

7

Beta strand

575 – 579

5

Beta strand

585 – 587

3

Helix

589 – 592

4

Helix

593 – 595

3

Turn

599 – 601

3

Helix

602 – 616

15

Beta strand

620 – 630

11

Helix

632 – 641

10

Turn

642 – 644

3

Beta strand

649 – 655

7

Helix

660 – 662

3

Helix

665 – 672

8

Turn

677 – 680

4

Helix

681 – 686

6

Helix

690 – 698

9

Beta strand

699 – 706

8

Beta strand

710 – 712

3

Helix

714 – 726

13

Beta strand

732 – 736

5

Helix

746 – 764

19

Sequences

	Sequence		Length	Mass (Da)
	P14740 [UniParc]. Last modified December 7, 2004. Version 2. Checksum: ED947174F1F3E440	FASTA	767	88,089
	10 20 30 40 50 60 MKTPWKVLLG LLGVAALVTI ITVPVVLLNK DEAAADSRRT YTLADYLKNT FRVKSYSLRW 70 80 90 100 110 120 VSDSEYLYKQ ENNILLFNAE HGNSSIFLEN STFEIFGDSI SDYSVSPDRL FVLLEYNYVK 130 140 150 160 170 180 QWRHSYTASY SIYDLNKRQL ITEEKIPNNT QWITWSQEGH KLAYVWKNDI YVKIEPHLPS 190 200 210 220 230 240 HRITSTGKEN VIFNGINDWV YEEEIFGAYS ALWWSPNGTF LAYAQFNDTG VPLIEYSFYS 250 260 270 280 290 300 DESLQYPKTV WIPYPKAGAV NPTVKFFIVN TDSLSSTTTT IPMQITAPAS VTTGDHYLCD 310 320 330 340 350 360 VAWVSEDRIS LQWLRRIQNY SVMAICDYDK TTLVWNCPTT QEHIETSATG WCGRFRPAEP 370 380 390 400 410 420 HFTSDGSSFY KIVSDKDGYK HICQFQKDRK PEQVCTFITK GAWEVISIEA LTSDYLYYIS 430 440 450 460 470 480 NEYKEMPGGR NLYKIQLTDH TNKKCLSCDL NPERCQYYSV SLSKEAKYYQ LGCRGPGLPL 490 500 510 520 530 540 YTLHRSTDQK ELRVLEDNSA LDKMLQDVQM PSKKLDFIVL NETRFWYQMI LPPHFDKSKK 550 560 570 580 590 600 YPLLIDVYAG PCSQKADAAF RLNWATYLAS TENIIVASFD GRGSGYQGDK IMHAINKRLG 610 620 630 640 650 660 TLEVEDQIEA ARQFLKMGFV DSKRVAIWGW SYGGYVTSMV LGSGSGVFKC GIAVAPVSRW 670 680 690 700 710 720 EYYDSVYTER YMGLPTPEDN LDHYRNSTVM SRAENFKQVE YLLIHGTADD NVHFQQSAQI 730 740 750 760 SKALVDAGVD FQAMWYTDED HGIASSTAHQ HIYSHMSHFL QQCFSLR

References

[1]	"Primary structure of rat liver dipeptidyl peptidase IV deduced from its cDNA and identification of the NH2-terminal signal sequence as the membrane-anchoring domain." Ogata S., Misumi Y., Ikehara Y. J. Biol. Chem. 264:3596-3601(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[2]	"cDNA cloning for a bile canaliculus domain-specific membrane glycoprotein of rat hepatocytes." Hong W., Doyle D. Proc. Natl. Acad. Sci. U.S.A. 84:7962-7966(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Membrane orientation of rat gp110 as studied by in vitro translation." Hong W.J., Doyle D. J. Biol. Chem. 263:16892-16898(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-40.
[4]	"Identification of the bile canalicular cell surface molecule GP110 as the ectopeptidase dipeptidyl peptidase IV: an analysis by tissue distribution, purification and N-terminal amino acid sequence." McCaughan G.W., Wickson J.E., Creswick P.F., Gorrell M.D. Hepatology 11:534-544(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 28-58, TISSUE SPECIFICITY.
[5]	"N-terminal amino acid sequence of the 60-kDa protein of rat kidney dipeptidyl peptidase IV." Iwaki-Egawa S., Watanabe Y., Fujimoto Y. Biol. Chem. Hoppe-Seyler 374:973-975(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 281-302, MUTAGENESIS OF GLY-629; TRP-630; SER-631; TRY-632 AND GLY-633. Tissue: Kidney.
[6]	"Identification of the active site residues in dipeptidyl peptidase IV by affinity labeling and site-directed mutagenesis." Ogata S., Misumi Y., Tsuji E., Takami N., Oda K., Ikehara Y. Biochemistry 31:2582-2587(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 624-648.
[7]	"Molecular dissection of the NH2-terminal signal/anchor sequence of rat dipeptidyl peptidase IV." Hong W., Doyle D. J. Cell Biol. 111:323-328(1990) [PubMed] [Europe PMC] [Abstract] Cited for: SIGNAL-ANCHOR.
[8]	"Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors." Longenecker K.L., Stewart K.D., Madar D.J., Jakob C.G., Fry E.H., Wilk S., Lin C.W., Ballaron S.J., Stashko M.A., Lubben T.H., Yong H., Pireh D., Pei Z., Basha F., Wiedeman P.E., von Geldern T.W., Trevillyan J.M., Stoll V.S. Biochemistry 45:7474-7482(2006) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 38-767 IN COMPLEX WITH INHIBITORS, GLYCOSYLATION AT ASN-83; ASN-90; ASN-227; ASN-319 AND ASN-521, DISULFIDE BONDS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

J04591 mRNA. Translation: AAA41096.1.
J02997 mRNA. Translation: AAA41272.1.

IPI

IPI00208422.

PIR

A39914.

RefSeq

NP_036921.1. NM_012789.1.

UniGene

Rn.91364.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2GBC	X-ray	2.80	A/B	38-767	[»]
2GBF	X-ray	3.10	A/B	38-767	[»]
2GBG	X-ray	3.00	A/B	38-767	[»]
2GBI	X-ray	3.30	A/B	38-767	[»]
2I3Z	X-ray	2.90	A/B	38-767	[»]
2OAE	X-ray	3.00	A/B	38-767	[»]
4FFV	X-ray	2.40	A/B	38-767	[»]
4FFW	X-ray	2.90	A/B	38-767	[»]

ProteinModelPortal

P14740.

SMR

P14740. Positions 38-767.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-4655516.

STRING

10116.ENSRNOP00000045536.

Protein family/group databases

MEROPS

S09.003.

Proteomic databases

PaxDb

P14740.

PRIDE

P14740.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

25253.

KEGG

rno:25253.

UCSC

RGD:2515. rat.

Organism-specific databases

CTD

1803.

RGD

2515. Dpp4.

Phylogenomic databases

eggNOG

COG1506.

HOGENOM

HOG000231875.

HOVERGEN

HBG005527.

InParanoid

P14740.

KO

K01278.

OrthoDB

EOG4XSKPF.

Enzyme and pathway databases

BRENDA

3.4.14.5. 5301.

Gene expression databases

ArrayExpress

P14740.

Genevestigator

P14740.

GermOnline

ENSRNOG00000030763. Rattus norvegicus.

Family and domain databases

InterPro

IPR002471. Pept_S9_AS.
IPR001375. Peptidase_S9.
IPR002469. Peptidase_S9B.
[Graphical view]

Pfam

PF00930. DPPIV_N. 1 hit.
PF00326. Peptidase_S9. 1 hit.
[Graphical view]

PROSITE

PS00708. PRO_ENDOPEP_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P14740.

ChEMBL

CHEMBL4653.

EvolutionaryTrace

P14740.

NextBio

605879.

Entry information

Entry name

DPP4_RAT

Accession

Primary (citable) accession number: P14740

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1990
Last sequence update:	December 7, 2004
Last modified:	April 3, 2013
This is version 126 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program