Dipeptidyl petidase IV related proteins (EC 3.4.14.5) (DPP IV) important for the activation or inactivation of extracellular endocrine paracrine and autocrine peptides. DPPIV is synonymous with CD26 (important in HIV infection). Some members lack active serine and are probably not enzymes. The prototype structure has a 8-bladed beta-propeller N-terminal domain which guide substrates to the active site and a transmembrane segment. DPP4 is a 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. The novel emerging coronavirus Middle East respiratory syndrome coronavirus (MERS-CoV) binds cells through DPP4. Mutations in the DPP6 gene are linked to autosomal dominant mental retardation.(Liao et al 2013). The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels. Structures of the complex are available (Kise et al.). DPP8 and DPP9 are cytosolic peptidases. Have dpp activity similar to dpp4. The first identified endogenous DPP9 substrate is the tumor epitope RU13442 (VPYGSFKHV). Inhibition or silencing of DPP9, but not DPP8, led to increased presentation of this antigen on MHC class I alleles to cytotoxic T-cells, linking DPP9 to the MHC class I antigen presentation pathway. Small ubiquitin-like protein modifier SUMO1 acts as an allosteric activator of DPP9. By binding to an armlike motif in DPP9; DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome. DPP9 interacts with a unique autoproteolytic domain found in NLRP1 and CARD8. Dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 is able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Sitagliptin, has little effect on microbial DPP4. daurisoline-d4 (Dau-d4) is a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.
Interpro : IPR001375 Peptidase_S9 , IPR002469 Peptidase S9B, dipeptidylpeptidase IV N-terminal , IPR031245 Dipeptidyl peptidase FAP FAP\/Dpf2
PIRSF : No PIRSF
Pdoc : No Pdoc
Pfam : PF00326 Peptidase_S9 , PF00930 DPPIV_N
Prints : No Print
EC Number : No EC Number
Structures (182)
Genes Proteins in DPP4N_Peptidase_S9 family (829)
Fragments of genes in DPP4N_Peptidase_S9 family (13)
Structures in DPP4N_Peptidase_S9 family (182)Substrates in DPP4N_Peptidase_S9 family (14)
Inhibitors in DPP4N_Peptidase_S9 family (157)
Title : Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target - Wang_2023_Science_381_eadd5787 |
Author(s) : Wang K , Zhang Z , Hang J , Liu J , Guo F , Ding Y , Li M , Nie Q , Lin J , Zhuo Y , Sun L , Luo X , Zhong Q , Ye C , Yun C , Zhang Y , Wang J , Bao R , Pang Y , Wang G , Gonzalez FJ , Lei X , Qiao J , Jiang C |
Ref : Science , 381 :eadd5787 , 2023 |
PubMedID: 37535747 |
Gene_locus related to this paper: bactn-BT4193 |
Title : New insights into the role of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 and their inhibitors - Cui_2022_Front.Pharmacol_13_1002871 |
Author(s) : Cui C , Tian X , Wei L , Wang Y , Wang K , Fu R |
Ref : Front Pharmacol , 13 :1002871 , 2022 |
PubMedID: 36172198 |
Gene_locus related to this paper: human-DPP8 , human-DPP9 |
Title : Structural basis of gating modulation of Kv4 channel complexes - Kise_2021_Nature__ |
Author(s) : Kise Y , Kasuya G , Okamoto HH , Yamanouchi D , Kobayashi K , Kusakizako T , Nishizawa T , Nakajo K , Nureki O |
Ref : Nature , : , 2021 |
PubMedID: 34552243 |
Gene_locus related to this paper: human-DPP6 |
Title : A novel structure associated with aging is augmented in the DPP6-KO mouse brain - Lin_2020_Acta.Neuropathol.Commun_8_197 |
Author(s) : Lin L , Petralia RS , Lake R , Wang YX , Hoffman DA |
Ref : Acta Neuropathologica Commun , 8 :197 , 2020 |
PubMedID: 33225987 |
Gene_locus related to this paper: human-DPP6 , mouse-DPP6 |
Title : A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice - Berger_2018_Endocrinol.Diabetes.Metab_1_e00002 |
Author(s) : Berger JP , SinhaRoy R , Pocai A , Kelly TM , Scapin G , Gao YD , Pryor KAD , Wu JK , Eiermann GJ , Xu SS , Zhang X , Tatosian DA , Weber AE , Thornberry NA , Carr RD |
Ref : Endocrinol Diabetes Metab , 1 :e00002 , 2018 |
PubMedID: 30815539 |
Gene_locus related to this paper: human-DPP4 |
Title : Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling - Rea_2017_Eur.J.Med.Chem_139_482 |
Author(s) : Rea D , Van Elzen R , De Winter H , Van Goethem S , Landuyt B , Luyten W , Schoofs L , Van der Veken P , Augustyns K , De Meester I , Fulop V , Lambeir AM |
Ref : Eur Journal of Medicinal Chemistry , 139 :482 , 2017 |
PubMedID: 28826083 |
Gene_locus related to this paper: porgi-DPP |
Title : Mapping the Specific Amino Acid Residues That Make Hamster DPP4 Functional as a Receptor for Middle East Respiratory Syndrome Coronavirus - van Doremalen_2016_J.Virol_90_5499 |
Author(s) : van Doremalen N , Miazgowicz KL , Munster VJ |
Ref : J Virol , 90 :5499 , 2016 |
PubMedID: 27030263 |
Gene_locus related to this paper: human-DPP4 |
Title : The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis - Waumans_2015_Front.Immunol_6_387 |
Author(s) : Waumans Y , Baerts L , Kehoe K , Lambeir AM , De Meester I |
Ref : Front Immunol , 6 :387 , 2015 |
PubMedID: 26300881 |
Title : Identification of residues on human receptor DPP4 critical for MERS-CoV binding and entry - Song_2014_Virology_471-473C_49 |
Author(s) : Song W , Wang Y , Wang N , Wang D , Guo J , Fu L , Shi X |
Ref : Virology , 471-473C :49 , 2014 |
PubMedID: 25461530 |
Gene_locus related to this paper: human-DPP4 |
Title : Distribution, classification, domain architectures and evolution of prolyl oligopeptidases in prokaryotic lineages - Kaushik_2014_BMC.Genomics_15_985 |
Author(s) : Kaushik S , Sowdhamini R |
Ref : BMC Genomics , 15 :985 , 2014 |
PubMedID: 25407321 |
Title : Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26 - Lu_2013_Nature_500_227 |
Author(s) : Lu G , Hu Y , Wang Q , Qi J , Gao F , Li Y , Zhang Y , Zhang W , Yuan Y , Bao J , Zhang B , Shi Y , Yan J , Gao GF |
Ref : Nature , 500 :227 , 2013 |
PubMedID: 23831647 |
Gene_locus related to this paper: human-DPP4 |
Title : Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4 - Wang_2013_Cell.Res_23_986 |
Author(s) : Wang N , Shi X , Jiang L , Zhang S , Wang D , Tong P , Guo D , Fu L , Cui Y , Liu X , Arledge KC , Chen YH , Zhang L , Wang X |
Ref : Cell Res , 23 :986 , 2013 |
PubMedID: 23835475 |
Gene_locus related to this paper: human-DPP4 |
Title : Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation - Liao_2013_Eur.J.Med.Genet_56_484 |
Author(s) : Liao C , Fu F , Li R , Yang WQ , Liao HY , Yan JR , Li J , Li SY , Yang X , Li DZ |
Ref : Eur Journal of Medical Genetics , 56 :484 , 2013 |
PubMedID: 23832105 |
Gene_locus related to this paper: human-DPP6 |
Title : A Novel SUMO1-specific Interacting Motif in Dipeptidyl Peptidase 9 (DPP9) That Is Important for Enzymatic Regulation - Pilla_2012_J.Biol.Chem_287_44320 |
Author(s) : Pilla E , Moller U , Sauer G , Mattiroli F , Melchior F , Geiss-Friedlander R |
Ref : Journal of Biological Chemistry , 287 :44320 , 2012 |
PubMedID: 23152501 |
Gene_locus related to this paper: human-DPP9 |
Title : The dipeptidyl peptidase IV family in cancer and cell biology - Yu_2010_FEBS.J_277_1126 |
Author(s) : Yu DM , Yao TW , Chowdhury S , Nadvi NA , Osborne B , Church WB , McCaughan GW , Gorrell MD |
Ref : Febs J , 277 :1126 , 2010 |
PubMedID: 20074209 |
Title : The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels - Dougherty_2009_Channels.(Austin)_3_122 |
Author(s) : Dougherty K , Tu L , Deutsch C , Covarrubias M |
Ref : Channels (Austin) , 3 :122 , 2009 |
PubMedID: 19372736 |
Gene_locus related to this paper: human-DPP6 |
Title : The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26 - Davoodi_2007_Proteomics_7_2300 |
Author(s) : Davoodi J , Kelly J , Gendron NH , Mackenzie AE |
Ref : Proteomics , 7 :2300 , 2007 |
PubMedID: 17549790 |
Title : The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices - Ghersi_2006_Cancer.Res_66_4652 |
Author(s) : Ghersi G , Zhao Q , Salamone M , Yeh Y , Zucker S , Chen WT |
Ref : Cancer Research , 66 :4652 , 2006 |
PubMedID: 16651416 |
Title : Expression, purification and preliminary crystallographic analysis of dipeptidyl peptidase IV from Porphyromonas gingivalis - Rea_2004_Acta.Crystallogr.D.Biol.Crystallogr_60_1871 |
Author(s) : Rea D , Lambeir AM , Kumagai Y , De Meester I , Scharpe S , Fulop V |
Ref : Acta Crystallographica D Biol Crystallogr , 60 :1871 , 2004 |
PubMedID: 15388936 |
Gene_locus related to this paper: porgi-DPP |
Title : Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases - Qi_2003_Biochem.J_373_179 |
Author(s) : Qi SY , Riviere PJ , Trojnar J , Junien JL , Akinsanya KO |
Ref : Biochemical Journal , 373 :179 , 2003 |
PubMedID: 12662155 |
Gene_locus related to this paper: human-DPP8 , human-DPP9 , human-DPP10 , mouse-dpp9 , mouse-dpp10 |
Title : Crystal structure of human dipeptidyl peptidase IV\/CD26 in complex with a substrate analog - Rasmussen_2003_Nat.Struct.Biol_10_19 |
Author(s) : Rasmussen HB , Branner S , Wiberg FC , Wagtmann N |
Ref : Nat Struct Biol , 10 :19 , 2003 |
PubMedID: 12483204 |
Gene_locus related to this paper: human-DPP4 |
Title : Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance - Conarello_2003_Proc.Natl.Acad.Sci.U.S.A_100_6825 |
Author(s) : Conarello SL , Li Z , Ronan J , Roy RS , Zhu L , Jiang G , Liu F , Woods J , Zycband E , Moller DE , Thornberry NA , Zhang BB |
Ref : Proc Natl Acad Sci U S A , 100 :6825 , 2003 |
PubMedID: 12748388 |
Gene_locus related to this paper: mouse-dpp4 |
Title : The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism - Engel_2003_Proc.Natl.Acad.Sci.U.S.A_100_5063 |
Author(s) : Engel M , Hoffmann T , Wagner L , Wermann M , Heiser U , Kiefersauer R , Huber R , Bode W , Demuth HU , Brandstetter H |
Ref : Proc Natl Acad Sci U S A , 100 :5063 , 2003 |
PubMedID: 12690074 |
Gene_locus related to this paper: pig-dpp4 |
Title : The structure and function of human dipeptidyl peptidase IV, possessing a unique eight-bladed beta-propeller fold - Hiramatsu_2003_Biochem.Biophys.Res.Commun_302_849 |
Author(s) : Hiramatsu H , Kyono K , Higashiyama Y , Fukushima C , Shima H , Sugiyama S , Inaka K , Yamamoto A , Shimizu R |
Ref : Biochemical & Biophysical Research Communications , 302 :849 , 2003 |
PubMedID: 12646248 |
Gene_locus related to this paper: human-DPP4 |
Title : Enzymatic properties of dipeptidyl aminopeptidase IV produced by the periodontal pathogen Porphyromonas gingivalis and its participation in virulence - Kumagai_2000_Infect.Immun_68_716 |
Author(s) : Kumagai Y , Konishi K , Gomi T , Yagishita H , Yajima A , Yoshikawa M |
Ref : Infect Immun , 68 :716 , 2000 |
PubMedID: 10639438 |
Gene_locus related to this paper: porgi-DPP |
Title : Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26 - Marguet_2000_Proc.Natl.Acad.Sci.U.S.A_97_6874 |
Author(s) : Marguet D , Baggio L , Kobayashi T , Bernard AM , Pierres M , Nielsen PF , Ribel U , Watanabe T , Drucker DJ , Wagtmann N |
Ref : Proc Natl Acad Sci U S A , 97 :6874 , 2000 |
PubMedID: 10823914 |
Title : Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity - Abbott_1999_FEBS.Lett_458_278 |
Author(s) : Abbott CA , McCaughan GW , Gorrell MD |
Ref : FEBS Letters , 458 :278 , 1999 |
PubMedID: 10570924 |
Title : Dipeptidyl-peptidase IV secreted by Aspergillus fumigatus, a fungus pathogenic to humans - Beauvais_1997_Infect.Immun_65_3042 |
Author(s) : Beauvais A , Monod M , Wyniger J , Debeaupuis JP , Grouzmann E , Brakch N , Svab J , Hovanessian AG , Latge JP |
Ref : Infect Immun , 65 :3042 , 1997 |
PubMedID: 9234752 |
Gene_locus related to this paper: aspfu-DPP4 |
Title : Direct association of adenosine deaminase with a T cell activation antigen, CD26 - Kameoka_1993_Science_261_466 |
Author(s) : Kameoka J , Tanaka T , Nojima Y , Schlossman SF , Morimoto C |
Ref : Science , 261 :466 , 1993 |
PubMedID: 8101391 |
Title : Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum - Mentlein_1993_Eur.J.Biochem_214_829 |
Author(s) : Mentlein R , Gallwitz B , Schmidt WE |
Ref : European Journal of Biochemistry , 214 :829 , 1993 |
PubMedID: 8100523 |