Dipeptidyl peptidase 9 substrates and their discovery: current progress and the application of mass spectrometry-based approaches

Claire H. Wilson; Hui Emma Zhang; Mark D. Gorrell; Catherine A. Abbott

doi:10.1515/hsz-2016-0174

Article

Dipeptidyl peptidase 9 substrates and their discovery: current progress and the application of mass spectrometry-based approaches

Claire H. Wilson
Claire H. Wilson is an NHMRC Early Career Research Fellow of the Centre for Cancer Biology in the University of South Australia. She completed her PhD in the laboratory of Associate Professor Catherine Abbott at Flinders University where she developed expertise in DPP enzymes. Her studies provided the first global identification into in vivo substrates of DPP8 and DPP9. During her PhD, she spent 18 months in the laboratory of Professor Christopher Overall at the University of British Columbia, Vancouver, BC, Canada where she developed expertise in the field of proteomics and its application to protease substrate discovery. Her broad research interests are in proteases, their roles in human health and disease and the application of ‘omics’-based technologies. Currently she is utilizing proteomics-based approaches for caspase substrate discovery. As an Early Career researcher she has authored 16 publications attracting ~200 citations and H index 7.
, Hui Emma Zhang
Hui Emma Zhang gained a Master’s of Applied Science in the Australian Center of Microscopy and Microanalysis (ACMM) in the University of Sydney and a PhD in Molecular Hepatology Laboratory in the Centenary Institute for Cancer Medicine and Cell Biology in Sydney, Australia, where she continues post-doc research. Her research interest is into the functions of an enzyme family called DPP4, and how to medically exploit this knowledge in chronic liver disease pathogenesis, liver cancer and diabetes.
, Mark D. Gorrell
Associate Professor Mark D. Gorrell of the University of Sydney Medical School heads the Molecular Hepatology Laboratory in the Centenary Institute for Cancer Medicine and Cell Biology in Sydney, Australia. He trained in cell biology, immunology and protein biochemistry during a PhD from Australian National University and postdoctoral studies at University of Melbourne and Johns Hopkins University. His research interests are in liver cancer prevention and treatment and disease pathogenesis. His research experience with liver fibrosis and cancer, diabetes, chronic liver disease pathogenesis, small RNA viruses, protein and protease biochemistry and cell biology now mainly centre upon the proteases DPP4, DPP9 and fibroblast activation protein. He has authored 123 publications attracting ~5,000 citations and H index 38.
and Catherine A. Abbott
Associate Professor Catherine A. Abbott heads her own laboratory at Flinders University, Adelaide South Australia. She worked and completed her PHD and post-doctoral training at the Molecular Hepatology Laboratory at the Centenary Institute 1991–2001. Her lab currently investigates the structure and function of the DPP4 gene family, using DPP inhibitors and DPP substrate discovery to study the role of these proteases in human diseases such as cancer, inflammation and metabolism. With over 25 years’ experience in this area she is internationally recognized as an expert in the DPP field. Dr Abbott also belongs to the Flinders Centre for Innovation in Cancer and is interested in novel treatments for the prevention and control of cancer in particular colorectal cancer. She has authored 65 publications attracting ~2316 citations and H index 24.

Published/Copyright: July 12, 2016

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From the journal Biological Chemistry Volume 397 Issue 9

Abstract

The enzyme members of the dipeptidyl peptidase 4 (DPP4) gene family have the very unusual capacity to cleave the post-proline bond to release dipeptides from the N-terminus of peptide/protein substrates. DPP4 and related enzymes are current and potential therapeutic targets in the treatment of type II diabetes, inflammatory conditions and cancer. Despite this, the precise biological function of individual dipeptidyl peptidases (DPPs), other than DPP4, and knowledge of their in vivo substrates remains largely unknown. For many years, identification of physiological DPP substrates has been difficult due to limitations in the available tools. Now, with advances in mass spectrometry based approaches, we can discover DPP substrates on a system wide-scale. Application of these approaches has helped reveal some of the in vivo natural substrates of DPP8 and DPP9 and their unique biological roles. In this review, we provide a general overview of some tools and approaches available for protease substrate discovery and their applicability to the DPPs with a specific focus on DPP9 substrates. This review provides comment upon potential approaches for future substrate elucidation.

Keywords: degradome; dipeptidyl peptidase; DPP9; N-terminomics; peptidomics; proteomics

Funding source: National Health and Medical Research Council

Award Identifier / Grant number: 1105238

Funding statement: CHW holds a National Health and Medical Research Council (NHMRC) Early Career Research Fellowship (1073771). Partial support derived from NHMRC grant 1105238 to MDG.

About the authors

Claire H. Wilson

Claire H. Wilson is an NHMRC Early Career Research Fellow of the Centre for Cancer Biology in the University of South Australia. She completed her PhD in the laboratory of Associate Professor Catherine Abbott at Flinders University where she developed expertise in DPP enzymes. Her studies provided the first global identification into in vivo substrates of DPP8 and DPP9. During her PhD, she spent 18 months in the laboratory of Professor Christopher Overall at the University of British Columbia, Vancouver, BC, Canada where she developed expertise in the field of proteomics and its application to protease substrate discovery. Her broad research interests are in proteases, their roles in human health and disease and the application of ‘omics’-based technologies. Currently she is utilizing proteomics-based approaches for caspase substrate discovery. As an Early Career researcher she has authored 16 publications attracting ~200 citations and H index 7.

Hui Emma Zhang

Hui Emma Zhang gained a Master’s of Applied Science in the Australian Center of Microscopy and Microanalysis (ACMM) in the University of Sydney and a PhD in Molecular Hepatology Laboratory in the Centenary Institute for Cancer Medicine and Cell Biology in Sydney, Australia, where she continues post-doc research. Her research interest is into the functions of an enzyme family called DPP4, and how to medically exploit this knowledge in chronic liver disease pathogenesis, liver cancer and diabetes.

Mark D. Gorrell

Associate Professor Mark D. Gorrell of the University of Sydney Medical School heads the Molecular Hepatology Laboratory in the Centenary Institute for Cancer Medicine and Cell Biology in Sydney, Australia. He trained in cell biology, immunology and protein biochemistry during a PhD from Australian National University and postdoctoral studies at University of Melbourne and Johns Hopkins University. His research interests are in liver cancer prevention and treatment and disease pathogenesis. His research experience with liver fibrosis and cancer, diabetes, chronic liver disease pathogenesis, small RNA viruses, protein and protease biochemistry and cell biology now mainly centre upon the proteases DPP4, DPP9 and fibroblast activation protein. He has authored 123 publications attracting ~5,000 citations and H index 38.

Catherine A. Abbott

Associate Professor Catherine A. Abbott heads her own laboratory at Flinders University, Adelaide South Australia. She worked and completed her PHD and post-doctoral training at the Molecular Hepatology Laboratory at the Centenary Institute 1991–2001. Her lab currently investigates the structure and function of the DPP4 gene family, using DPP inhibitors and DPP substrate discovery to study the role of these proteases in human diseases such as cancer, inflammation and metabolism. With over 25 years’ experience in this area she is internationally recognized as an expert in the DPP field. Dr Abbott also belongs to the Flinders Centre for Innovation in Cancer and is interested in novel treatments for the prevention and control of cancer in particular colorectal cancer. She has authored 65 publications attracting ~2316 citations and H index 24.

Acknowledgments

CHW holds a National Health and Medical Research Council (NHMRC) Early Career Research Fellowship (1073771). Partial support derived from NHMRC grant 1105238 to MDG.

References

Abbatiello, S.E., Schilling, B., Mani, D.R., Zimmerman, L.J., Hall, S.C., MacLean, B., Albertolle, M., Allen, S., Burgess, M., Cusack, M.P., et al. (2015). Large-scale interlaboratory study to develop, analytically validate and apply highly multiplexed, quantitative peptide assays to measure cancer-relevant proteins in plasma. Mol. Cell Proteomics 14, 2357–2374.10.1074/mcp.M114.047050Search in Google Scholar PubMed PubMed Central

Abbott, C.A., Yu, D.M.T., Woollatt, E., Sutherland, G.R., McCaughan, G.W., and Gorrell, M.D. (2000). Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur. J. Biochem. 267, 6140–6150.10.1046/j.1432-1327.2000.01617.xSearch in Google Scholar PubMed

Agard, N.J., Mahrus, S., Trinidad, J.C., Lynn, A., Burlingame, A.L., and Wells, J.A. (2012). Global kinetic analysis of proteolysis via quantitative targeted proteomics. Proc. Natl. Acad. Sci. USA 109, 1913–1918.10.1073/pnas.1117158109Search in Google Scholar PubMed PubMed Central

Ajami, K., Abbott, C.A., McCaughan, G.W., and Gorrell, M.D. (2004). Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity. Biochim. Biophys. Acta 1679, 18–28.10.1016/j.bbaexp.2004.03.010Search in Google Scholar PubMed

Ajami, K., Pitman, M.R., Wilson, C.H., Park, J., Menz, R.I., Starr, A.E., Cox, J.H., Abbott, C.A., Overall, C.M., and Gorrell, M.D. (2008). Stromal cell-derived factors 1α and 1β, inflammatory protein-10 and interferon-inducible T cell chemo-attractant are novel substrates of dipeptidyl peptidase 8. FEBS Lett. 582, 819–825.10.1016/j.febslet.2008.02.005Search in Google Scholar PubMed

Auf dem Keller, U., Prudova, A., Eckhard, U., Fingleton, B., and Overall, C.M. (2013). Systems-level analysis of proteolytic events in increased vascular permeability and complement activation in skin inflammation. Sci. Signal. 6, rs2.10.1126/scisignal.2003512Search in Google Scholar PubMed PubMed Central

Bjelke, J.R., Christensen, J., Nielsen, P.F., Branner, S., Kanstrup, A.B., Wagtmann, N., and Rasmussen, H.B. (2006). Dipeptidyl peptidases 8 and 9: specificity and molecular characterization compared with dipeptidyl peptidase IV. Biochem. J. 396, 391–399.10.1042/BJ20060079Search in Google Scholar PubMed PubMed Central

Chen, X. (2006). Biochemical properties of recombinant prolyl dipeptidases DPP-IV and DPP8. Adv. Exp. Med. Biol. 575, 27–32.10.1007/0-387-32824-6_3Search in Google Scholar PubMed

Chen, Y., Gall, M.G., Zhang, H., Keane, F.M., McCaughan, G.W., Yu, D.M., and Gorrell, M.D. (2016). Dipeptidyl peptidase 9 enzymatic activity influences the expression of neonatal metabolic genes. Exp. Cell Res. 342, 72–82.10.1016/j.yexcr.2016.02.020Search in Google Scholar PubMed

Crooks, G.E., Hon, G., Chandonia, J.M., and Brenner, S.E. (2004). WebLogo: a sequence logo generator. Genome Res. 14, 1188–1190.10.1101/gr.849004Search in Google Scholar PubMed PubMed Central

Deacon, C.F. (2004). Circulation and degradation of GIP and GLP-1. Horm. Metab. Res. 36, 761–765.10.1055/s-2004-826160Search in Google Scholar

Deacon, C.F. and Lebovitz, H.E. (2016). Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes. Metab. 18, 333–347.10.1111/dom.12610Search in Google Scholar

Demon, D., Van Damme, P., Vanden Berghe, T., Deceuninck, A., Van Durme, J., Verspurten, J., Helsens, K., Impens, F., Wejda, M., Schymkowitz, J., et al. (2009). Proteome-wide substrate analysis indicates substrate exclusion as a mechanism to generate caspase-7 versus caspase-3 specificity. Mol. Cell Proteomics 8, 2700–2714.10.1074/mcp.M900310-MCP200Search in Google Scholar

Dix, M.M., Simon, G.M., and Cravatt, B.F. (2008). Global mapping of the topography and magnitude of proteolytic events in apoptosis. Cell 134, 679–691.10.1016/j.cell.2008.06.038Search in Google Scholar

Donahue, R.N., Duncan, B.B., Fry, T.J., Jones, B., Bachovchin, W.W., Kiritsy, C.P., Lai, J.H., Wu, W., Zhao, P., Liu, Y., et al. (2014). A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines. Vaccine 32, 3223–3231.10.1016/j.vaccine.2014.04.008Search in Google Scholar

Duncan, B.B., Highfill, S.L., Qin, H., Bouchkouj, N., Larabee, S., Zhao, P., Woznica, I., Liu, Y., Li, Y., Wu, W., et al. (2013). A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy. J. Immunother. 36, 400–411.10.1097/CJI.0b013e3182a80213Search in Google Scholar

Durinx, C., Lambeir, A.M., Bosmans, E., Falmagne, J.B., Berghmans, R., Haemers, A., Scharpe, S., and De Meester, I. (2000). Molecular characterization of dipeptidyl peptidase activity in serum – soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur. J. Biochem. 267, 5608–5613.10.1046/j.1432-1327.2000.01634.xSearch in Google Scholar

Edwards, D.R., Handsley, M.M., and Pennington, C.J. (2008). The ADAM metalloproteinases. Mol. Aspects Med. 29, 258–289.10.1016/j.mam.2008.08.001Search in Google Scholar

Fischer, G., Heins, J., and Barth, A. (1983). The conformation around the peptide bond between the P1- and P2-positions is important for catalytic activity of some proline-specific proteases. Biochim. Biophys. Acta 742, 452–462.10.1016/0167-4838(83)90261-3Search in Google Scholar

Frerker, N., Wagner, L., Wolf, R., Heiser, U., Hoffmann, T., Rahfeld, J.U., Schade, J., Karl, T., Naim, H.Y., Alfalah, M., et al. (2007). Neuropeptide Y (NPY) cleaving enzymes: structural and functional homologues of dipeptidyl peptidase 4. Peptides 28, 257–268.10.1016/j.peptides.2006.09.027Search in Google Scholar PubMed

Gall, M.G., Chen, Y., Vieira de Ribeiro, A.J., Zhang, H., Bailey, C.G., Spielman, D.S., Yu, D.M., and Gorrell, M.D. (2013). Targeted inactivation of dipeptidyl peptidase 9 enzymatic activity causes mouse neonate lethality. PloS One 8, e78378.10.1371/journal.pone.0078378Search in Google Scholar

Garcia-Horsman, J.A., Mannisto, P.T., and Venalainen, J.I. (2007). On the role of prolyl oligopeptidase in health and disease. Neuropeptides 41, 1–24.10.1016/j.npep.2006.10.004Search in Google Scholar

Geiss-Friedlander, R., Parmentier, N., Moller, U., Urlaub, H., Van den Eynde, B.J., and Melchior, F. (2009). The cytoplasmic peptidase DPP9 is rate-limiting for degradation of proline-containing peptides. J. Biol. Chem. 284, 27211–27219.10.1074/jbc.M109.041871Search in Google Scholar

Gevaert, K., Van Damme, J., Goethals, M., Thomas, G.R., Hoorelbeke, B., Demol, H., Martens, L., Puype, M., Staes, A., and Vandekerckhove, J. (2002). Chromatographic isolation of methionine-containing peptides for gel-free proteome analysis: identification of more than 800 Escherichia coli proteins. Mol Cell. Proteomics 1, 896–903.10.1074/mcp.M200061-MCP200Search in Google Scholar

Gevaert, K., Goethals, M., Martens, L., Van Damme, J., Staes, A., Thomas, G.R., and Vandekerckhove, J. (2003). Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nat. Biotechnol. 21, 566–569.10.1038/nbt810Search in Google Scholar

Grobe, N., Elased, K.M., Cool, D.R., and Morris, M. (2012). Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney. Am. J. Physiol. Endocrinol. Metab. 302, E1016–1024.10.1152/ajpendo.00515.2011Search in Google Scholar

Han, R., Wang, X., Bachovchin, W., Zukowska, Z., and Osborn, J.W. (2015). Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation. Sci. Rep. 5, 12348.10.1038/srep12348Search in Google Scholar

Hoppe, T., Rape, M., and Jentsch, S. (2001). Membrane-bound transcription factors: regulated release by RIP or RUP. Curr. Opin. Cell Biol. 13, 344–348.10.1016/S0955-0674(00)00218-0Search in Google Scholar

Hopsu-Havu, V.K., Rintola, P., and Glenner, G.G. (1968). A hog kidney aminopeptidase liberating N-terminal dipeptides. Partial purification and characteristics. Acta Chem. Scand. 22, 299–308.10.3891/acta.chem.scand.22-0299Search in Google Scholar PubMed

Huesgen, P.F., Lange, P.F., Rogers, L.D., Solis, N., Eckhard, U., Kleifeld, O., Goulas, T., Gomis-Ruth, F.X., and Overall, C.M. (2015). LysargiNase mirrors trypsin for protein C-terminal and methylation-site identification. Nat. Methods 12, 55–58.10.1038/nmeth.3177Search in Google Scholar PubMed

Jost, M.M., Lamerz, J., Tammen, H., Menzel, C., De Meester, I., Lambeir, A.M., Augustyns, K., Scharpe, S., Zucht, H.D., Rose, H., et al. (2009). In vivo profiling of DPP4 inhibitors reveals alterations in collagen metabolism and accumulation of an amyloid peptide in rat plasma. Biochem. Pharmacol. 77, 228–237.10.1016/j.bcp.2008.09.032Search in Google Scholar PubMed

Justa-Schuch, D., Moller, U., and Geiss-Friedlander, R. (2014). The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus. Cell Mol. Life Sci. 71, 3611–3626.10.1007/s00018-014-1591-6Search in Google Scholar PubMed

Kang, N.S., Ahn, J.H., Kim, S.S., Chae, C.H., and Yoo, S.E. (2007). Docking-based 3D-QSAR study for selectivity of DPP4, DPP8, and DPP9 inhibitors. Bioorg. Med. Chem. Lett. 17, 3716–3721.10.1016/j.bmcl.2007.04.031Search in Google Scholar PubMed

Keane, F.M., Nadvi, N.A., Yao, T.W., and Gorrell, M.D. (2011). Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J. 278, 1316–1332.10.1111/j.1742-4658.2011.08051.xSearch in Google Scholar PubMed

Keane, F.M., Yao, T.W., Seelk, S., Gall, M.G., Chowdhury, S., Poplawski, S.E., Lai, J.H., Li, Y., Wu, W., Farrell, P., et al. (2013). Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. FEBS Open Bio. 4, 43–54.10.1016/j.fob.2013.12.001Search in Google Scholar PubMed PubMed Central

Kirby, M., Yu, D.M., O’Connor, S., and Gorrell, M.D. (2010). Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin. Sci. (Lond) 118, 31–41.10.1042/CS20090047Search in Google Scholar PubMed

Kirstein-Miles, J., and Morimoto, R.I. (2010). Peptides signal mitochondrial stress. Cell Metab. 11, 177–178.10.1016/j.cmet.2010.02.011Search in Google Scholar PubMed

Kleifeld, O., Doucet, A., auf dem Keller, U., Prudova, A., Schilling, O., Kainthan, R.K., Starr, A.E., Foster, L.J., Kizhakkedathu, J.N., and Overall, C.M. (2010). Isotopic labeling of terminal amines in complex samples identifies protein N-termini and protease cleavage products. Nat. Biotechnol. 28, 281–288.10.1038/nbt.1611Search in Google Scholar PubMed

Kleifeld, O., Doucet, A., Prudova, A., auf dem Keller, U., Gioia, M., Kizhakkedathu, J.N., and Overall, C.M. (2011). Identifying and quantifying proteolytic events and the natural N terminome by terminal amine isotopic labeling of substrates. Nat. Protoc. 6, 1578–1611.10.1038/nprot.2011.382Search in Google Scholar PubMed

Klein, T., Fung, S.Y., Renner, F., Blank, M.A., Dufour, A., Kang, S., Bolger-Munro, M., Scurll, J.M., Priatel, J.J., Schweigler, P., et al. (2015). The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling. Nat. Commun. 6, 8777.10.1038/ncomms9777Search in Google Scholar PubMed PubMed Central

Klemann, C., Wagner, L., Stephan, M., and von Horsten, S. (2016). Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin. Exp. Immunol. 185, 1–21.10.1111/cei.12781Search in Google Scholar PubMed PubMed Central

Lambeir, A.M., Proost, P., Durinx, C., Bal, G., Senten, K., Augustyns, K., Scharpe, S., Van Damme, J., and De Meester, I. (2001). Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. J. Biol. Chem. 276, 29839–29845.10.1074/jbc.M103106200Search in Google Scholar PubMed

Lamkanfi, M., Kanneganti, T.D., Van Damme, P., Vanden Berghe, T., Vanoverberghe, I., Vandekerckhove, J., Vandenabeele, P., Gevaert, K., and Nunez, G. (2008). Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. Mol. Cell Proteomics 7, 2350–2363.10.1074/mcp.M800132-MCP200Search in Google Scholar PubMed PubMed Central

Lee, K.N., Jackson, K.W., Christiansen, V.J., Chung, K.H., and McKee, P.A. (2004). A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion. Blood 103, 3783–3788.10.1182/blood-2003-12-4240Search in Google Scholar PubMed

Lee, H.J., Chen, Y.S., Chou, C.Y., Chien, C.H., Lin, C.H., Chang, G.G., and Chen, X. (2006). Investigation of the dimer interface and substrate specificity of prolyl dipeptidase DPP8. J. Biol. Chem. 281, 38653–38662.10.1074/jbc.M603895200Search in Google Scholar PubMed

Lone, A.M., Nolte, W.M., Tinoco, A.D., and Saghatelian, A. (2010). Peptidomics of the prolyl peptidases. The AAPS J. 12, 483–491.10.1208/s12248-010-9208-ySearch in Google Scholar PubMed PubMed Central

Lopez-Otin, C., and Overall, C.M. (2002). Protease degradomics: a new challenge for proteomics. Nat. Rev. Mol. Cell Biol. 3, 509–519.10.1038/nrm858Search in Google Scholar PubMed

Lu, C., Tilan, J.U., Everhart, L., Czarnecka, M., Soldin, S.J., Mendu, D.R., Jeha, D., Hanafy, J., Lee, C.K., Sun, J., Izycka-Swieszewska, E., Toretsky, J.A., Kitlinska, J. (2011). Dipeptidyl peptidases as survival factors in ewing sarcoma family tumors. J. Biol. Chem. 286, 27494–27505.10.1074/jbc.M111.224089Search in Google Scholar PubMed PubMed Central

Maes, M.B., Scharpe, S., and De Meester, I. (2007). Dipeptidyl peptidase II (DPPII), a review. Clin. Chim. Acta. 380, 31–49.10.1016/j.cca.2007.01.024Search in Google Scholar PubMed

Marino, G., Eckhard, U., and Overall, C.M. (2015). Protein termini and their modifications revealed by positional proteomics. ACS Chem. Biol. 10, 1754–1764.10.1021/acschembio.5b00189Search in Google Scholar PubMed

Matheeussen, V., Waumans, Y., Martinet, W., Van Goethem, S., Van der Veken, P., Scharpe, S., Augustyns, K., De Meyer, G.R., and De Meester, I. (2013). Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis. Basic Res. Cardiol. 108, 350.10.1007/s00395-013-0350-4Search in Google Scholar PubMed

Mentlein, R., Gallwitz, B., and Schmidt, W.E. (1993). 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. Eur. J. Biochem. 214, 829–835.10.1111/j.1432-1033.1993.tb17986.xSearch in Google Scholar PubMed

Nolte, W.M., Tagore, D.M., Lane, W.S., and Saghatelian, A. (2009). Peptidomics of prolyl endopeptidase in the central nervous system. Biochem. 48, 11971–11981.10.1021/bi901637cSearch in Google Scholar PubMed PubMed Central

O’Donoghue, A.J., Eroy-Reveles, A.A., Knudsen, G.M., Ingram, J., Zhou, M., Statnekov, J.B., Greninger, A.L., Hostetter, D.R., Qu, G., Maltby, D.A., et al. (2012). Global identification of peptidase specificity by multiplex substrate profiling. Nat. Methods 9, 1095–1100.10.1038/nmeth.2182Search in Google Scholar PubMed PubMed Central

Park, J., Knott, H.M., Nadvi, N.A., Collyer, C.A., Wang, X.M., Church, W.B., and Gorrell, M.D. (2008). Reversible inactivation of human dipeptidyl peptidases 8 and 9 by oxidation. Open Enzym. Inhib. J. 1, 52–60.10.2174/1874940200801010052Search in Google Scholar

Pitman, M.R., Menz, R.I., and Abbott, C.A. (2010). Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8). Biol. Chem. 391, 959–972.10.1515/bc.2010.111Search in Google Scholar PubMed

Plasman, K., Van Damme, P., and Gevaert, K. (2013). Contemporary positional proteomics strategies to study protein processing. Curr. Opin. Chem. Biol. 17, 66–72.10.1016/j.cbpa.2012.11.026Search in Google Scholar PubMed

Poreba, M., Mihelic, M., Krai, P., Rajkovic, J., Krezel, A., Pawelczak, M., Klemba, M., Turk, D., Turk, B., Latajka, R., et al. (2014). Unnatural amino acids increase activity and specificity of synthetic substrates for human and malarial cathepsin C. Amino Acids 46, 931–943.10.1007/s00726-013-1654-2Search in Google Scholar PubMed PubMed Central

Prudova, A., Serrano, K., Eckhard, U., Fortelny, N., Devine, D.V., and Overall, C.M. (2014). TAILS N-terminomics of human platelets reveals pervasive metalloproteinase-dependent proteolytic processing in storage. Blood 124, e49–60.10.1182/blood-2014-04-569640Search in Google Scholar PubMed PubMed Central

Qi, S.Y., Riviere, P.J., Trojnar, J., Junien, J.L., and Akinsanya, K.O. (2003). Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Biochem. J. 373, 179–189.10.1042/bj20021914Search in Google Scholar PubMed PubMed Central

Rasmussen, H.B., Branner, S., Wiberg, F.C., and Wagtmann, N. (2003). Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat. Struct. Biol. 10, 19–25.10.1038/nsb882Search in Google Scholar PubMed

Rawlings, N.D., Barrett, A.J., and Finn, R. (2016). Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 44, D343–350.10.1093/nar/gkv1118Search in Google Scholar PubMed PubMed Central

Rettig, W.J., Garin-Chesa, P., Healey, J.H., Su, S.L., Ozer, H.L., Schwab, M., Albino, A.P., and Old, L.J. (1993). Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 53, 3327–3335.Search in Google Scholar

Rogers, L.D., and Overall, C.M. (2013). Proteolytic post-translational modification of proteins: proteomic tools and methodology. Mol. Cell Proteomics 12, 3532–3542.10.1074/mcp.M113.031310Search in Google Scholar PubMed PubMed Central

Rummey, C., and Metz, G. (2007). Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site. Proteins 66, 160–171.10.1002/prot.21138Search in Google Scholar PubMed

Rut, W., Kasperkiewicz, P., Byzia, A., Poreba, M., Groborz, K., and Drag, M. (2015). Recent advances and concepts in substrate specificity determination of proteases using tailored libraries of fluorogenic substrates with unnatural amino acids. Biol. Chem. 396, 329–337.10.1515/hsz-2014-0315Search in Google Scholar PubMed

Sabino, F., Hermes, O., Egli, F.E., Kockmann, T., Schlage, P., Croizat, P., Kizhakkedathu, J.N., Smola, H., and auf dem Keller, U. (2015). In vivo assessment of protease dynamics in cutaneous wound healing by degradomics analysis of porcine wound exudates. Mol. Cell Proteomics 14, 354–370.10.1074/mcp.M114.043414Search in Google Scholar PubMed PubMed Central

Schade, J., Stephan, M., Schmiedl, A., Wagner, L., Niestroj, A.J., Demuth, H.U., Frerker, N., Klemann, C., Raber, K.A., Pabst, R., et al. (2008). Regulation of expression and function of dipeptidyl peptidase 4 (DP4), DP8/9, and DP10 in allergic responses of the lung in rats. J. Histochem. Cytochem. 56, 147–155.10.1369/jhc.7A7319.2007Search in Google Scholar PubMed PubMed Central

Schilling, O., Huesgen, P.F., Barre, O., and Overall, C.M. (2011). Identification and relative quantification of native and proteolytically generated protein C-termini from complex proteomes: C-terminome analysis. Methods Mol. Biol. 781, 59–69.10.1007/978-1-61779-276-2_4Search in Google Scholar PubMed

Schlauderer, G.J., and Schulz, G.E. (1996). The structure of bovine mitochondrial adenylate kinase: comparison with isoenzymes in other compartments. Protein Sci. 5, 434–441.10.1002/pro.5560050304Search in Google Scholar PubMed PubMed Central

Soisson, S.M., Patel, S.B., Abeywickrema, P.D., Byrne, N.J., Diehl, R.E., Hall, D.L., Ford, R.E., Reid, J.C., Rickert, K.W., Shipman, J.M., et al. (2010). Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase. BMC Struct. Biol. 10, 16.10.1186/1472-6807-10-16Search in Google Scholar PubMed PubMed Central

Staes, A., Impens, F., Van Damme, P., Ruttens, B., Goethals, M., Demol, H., Timmerman, E., Vandekerckhove, J., and Gevaert, K. (2011). Selecting protein N-terminal peptides by combined fractional diagonal chromatography. Nat. Protoc. 6, 1130–1141.10.1038/nprot.2011.355Search in Google Scholar

Sulda, M.L., Abbott, C.A., Macardle, P.J., Hall, R.K., and Kuss, B.J. (2010). Expression and prognostic assessment of dipeptidyl peptidase IV and related enzymes in B-cell chronic lymphocytic leukemia. Cancer Biol. Ther. 10, 180–189.10.4161/cbt.10.2.12168Search in Google Scholar

Tagore, D.M., Nolte, W.M., Neveu, J.M., Rangel, R., Guzman-Rojas, L., Pasqualini, R., Arap, W., Lane, W.S., and Saghatelian, A. (2009). Peptidase substrates via global peptide profiling. Nat. Chem. Biol. 5, 23–25.10.1038/nchembio.126Search in Google Scholar

Tang, H.K., Tang, H.Y., Hsu, S.C., Chu, Y.R., Chien, C.H., Shu, C.H., and Chen, X. (2009). Biochemical properties and expression profile of human prolyl dipeptidase DPP9. Arch. Biochem. Biophys 485, 120–127.10.1016/j.abb.2009.02.015Search in Google Scholar

Thoma, R., Loffler, B., Stihle, M., Huber, W., Ruf, A., and Hennig, M. (2003). Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. Structure 11, 947–959.10.1016/S0969-2126(03)00160-6Search in Google Scholar

Tinoco, A.D., Tagore, D.M., and Saghatelian, A. (2010). Expanding the dipeptidyl peptidase 4-regulated peptidome via an optimized peptidomics platform. J. Am. Chem. Soc. 132, 3819–3830.10.1021/ja909524eSearch in Google Scholar PubMed PubMed Central

Van Damme, P., Martens, L., Van Damme, J., Hugelier, K., Staes, A., Vandekerckhove, J., and Gevaert, K. (2005). Caspase-specific and nonspecific in vivo protein processing during Fas-induced apoptosis. Nat. Methods 2, 771–777.10.1038/nmeth792Search in Google Scholar PubMed

Van Damme, P., Maurer-Stroh, S., Plasman, K., Van Durme, J., Colaert, N., Timmerman, E., De Bock, P.J., Goethals, M., Rousseau, F., Schymkowitz, J., et al. (2009). Analysis of protein processing by N-terminal proteomics reveals novel species-specific substrate determinants of granzyme B orthologs. Mol. Cell Proteomics 8, 258–272.10.1074/mcp.M800060-MCP200Search in Google Scholar PubMed

Van Damme, P., Maurer-Stroh, S., Hao, H., Colaert, N., Timmerman, E., Eisenhaber, F., Vandekerckhove, J., and Gevaert, K. (2010a). The substrate specificity profile of human granzyme A. Biol. Chem. 391, 983–997.10.1515/bc.2010.096Search in Google Scholar

Van Damme, P., Staes, A., Bronsoms, S., Helsens, K., Colaert, N., Timmerman, E., Aviles, F.X., Vandekerckhove, J., and Gevaert, K. (2010b). Complementary positional proteomics for screening substrates of endo- and exoproteases. Nat. Methods 7, 512–515.10.1038/nmeth.1469Search in Google Scholar PubMed

Varshavsky, A. (2011). The N-end rule pathway and regulation by proteolysis. Protein Sci. 20, 1298–1345.10.1002/pro.666Search in Google Scholar PubMed PubMed Central

Venne, A.S., Solari, F.A., Faden, F., Paretti, T., Dissmeyer, N., and Zahedi, R.P. (2015). An improved workflow for quantitative N-terminal charge-based fractional diagonal chromatography (ChaFRADIC) to study proteolytic events in Arabidopsis thaliana. Proteomics 15, 2458–2469.10.1002/pmic.201500014Search in Google Scholar PubMed

Vizovisek, M., Vidmar, R., Fonovic, M., and Turk, B. (2016). Current trends and challenges in proteomic identification of protease substrates. Biochimie 122, 77–87.10.1016/j.biochi.2015.10.017Search in Google Scholar PubMed

Wagner, L., Klemann, C., Stephan, M., and von Horsten, S. (2016). Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin. Exp. Immunol. 184, 265–283.10.1111/cei.12757Search in Google Scholar PubMed PubMed Central

Waumans, Y., Baerts, L., Kehoe, K., Lambeir, A.M., and De Meester, I. (2015). The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis. Front. Immunol. 6, 387.10.3389/fimmu.2015.00387Search in Google Scholar PubMed PubMed Central

Waumans, Y., Vliegen, G., Maes, L., Rombouts, M., Declerck, K., Van Der Veken, P., Vanden Berghe, W., De Meyer, G.R., Schrijvers, D., and De Meester, I. (2016). The dipeptidyl peptidases 4, 8, and 9 in mouse monocytes and macrophages: DPP8/9 inhibition attenuates M1 macrophage activation in mice. Inflammation 39, 413–424.10.1007/s10753-015-0263-5Search in Google Scholar PubMed

Wilson, C.H., Indarto, D., Doucet, A., Pogson, L.D., Pitman, M.R., McNicholas, K., Menz, R.I., Overall, C.M., and Abbott, C.A. (2013). Identifying natural substrates for dipeptidyl peptidases 8 and 9 using terminal amine isotopic labeling of substrates (TAILS) reveals in vivo roles in cellular homeostasis and energy metabolism. J. Biol. Chem. 288, 13936–13949.10.1074/jbc.M112.445841Search in Google Scholar PubMed PubMed Central

Yates, N.A., Deyanova, E.G., Geissler, W., Wiener, M.C., Sachs, J.R., Wong, K.K., Thornberry, N.A., Roy, R.S., Settlage, R.E., and Hendrickson, R.C. (2007). Identification of peptidase substrates in human plasma by FTMS based differential mass spectrometry. Int. J. Mass Spectrom. 259, 174–183.10.1016/j.ijms.2006.09.020Search in Google Scholar

Yu, D.M., Ajami, K., Gall, M.G., Park, J., Lee, C.S., Evans, K.A., McLaughlin, E.A., Pitman, M.R., Abbott, C.A., McCaughan, G.W., et al. (2009). The in vivo expression of dipeptidyl peptidases 8 and 9. J. Histochem. Cytochem. 57, 1025–1040.10.1369/jhc.2009.953760Search in Google Scholar PubMed PubMed Central

Zhang, H., Chen, Y., Keane, F.M., and Gorrell, M.D. (2013). Advances in understanding the expression and function of dipeptidyl peptidase 8 and 9. Mol. Cancer Res. 11, 1487–1496.10.1158/1541-7786.MCR-13-0272Search in Google Scholar PubMed

Zhang, H., Chen, Y., Wadham, C., McCaughan, G.W., Keane, F.M., and Gorrell, M.D. (2015a). Dipeptidyl peptidase 9 subcellular localization and a role in cell adhesion involving focal adhesion kinase and paxillin. Biochim. Biophys. Acta 1853, 470–480.10.1016/j.bbamcr.2014.11.029Search in Google Scholar PubMed

Zhang, H., Maqsudi, S., Rainczuk, A., Duffield, N., Lawrence, J., Keane, F.M., Justa-Schuch, D., Geiss-Friedlander, R., Gorrell, M.D., and Stephens, A.N. (2015b). Identification of novel dipeptidyl peptidase 9 substrates by two-dimensional differential in-gel electrophoresis. FEBS J. 282, 3737–3757.10.1111/febs.13371Search in Google Scholar PubMed

Received: 2016-4-14

Accepted: 2016-7-4

Published Online: 2016-7-12

Published in Print: 2016-9-1

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Articles in the same Issue

https://doi.org/10.1515/hsz-2016-0174

Keywords for this article

degradome; dipeptidyl peptidase; DPP9; N-terminomics; peptidomics; proteomics