Homodimerization via a Leucine Zipper Motif is Required for Enzymatic Activity of Quiescent cell Proline Dipeptidase

Chiravuri, Murali; Lee, Henry; Mathieu, Suzanne L.; Huber, Brigitte

doi:10.1074/jbc.m005445200

Cited by 15 publications

(16 citation statements)

References 24 publications

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“…It was previously shown that homodimerization is required for enzymatic activity of DPP7 and that residues from a leucine zipper motif are involved in oligomerization [12]. According to a PISA analysis [20] of all three crystal lattices, DPP7 may form stable dimers in solution.…”

Section: Resultsmentioning

confidence: 99%

“…The predicted catalytic triad comprises Ser162, Asp418 and His443. DPP7 is the first reported protease that contains a leucine zipper motif through which the functional homodimer has been predicted to be formed [12]. Two N-glycosylation sites, Asn50 and Asn315, have been experimentally characterized and four more sites predicted by sequence analysis [13].…”

Section: Introductionmentioning

confidence: 99%

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Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

et al. 2012

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Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/β-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The “specificity domains” are structurally also completely different exhibiting a β-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

et al. 2012

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“…The soluble serine protease contains a proform and has a length of 492 amino acids with a molecular weight of 58 kDa [77,78]. Glycosylation and dimerization are required for the catalytic activity and the latter occurs via a leucine zipper motif, which is novel for proteases [79]. The homodimer is located in cellular vesicles that are distinct from lysosomes and secretion is regulated by an increased Ca 21 flux [77].…”

Section: Non-related Dpp4-like Enzymesmentioning

confidence: 99%

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

Wagner¹,

Klemann²,

Stephan

et al. 2016

Clinical and Experimental Immunology

109

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SummaryDipeptidyl peptidase (DPP) 4 (CD26, DPP4) is a multi-functional protein involved in T cell activation by co-stimulation via its association with adenosine deaminase (ADA), caveolin-1, CARMA-1, CD45, mannose-6-phosphate/insulin growth factor-II receptor (M6P/IGFII-R) and C-X-C motif receptor 4 (CXC-R4). The proline-specific dipeptidyl peptidase also modulates the bioactivity of several chemokines. However, a number of enzymes displaying either DPP4-like activities or representing structural homologues have been discovered in the past two decades and are referred to as DPP4 activity and/or structure homologue (DASH) proteins. Apart from DPP4, DASH proteins include fibroblast activation protein alpha (FAP), DPP8, DPP9, DPP4-like protein 1 (DPL1, DPP6, DPPX L, DPPX S), DPP4-like protein 2 (DPL2, DPP10) from the DPP4-gene family S9b and structurally unrelated enzyme DPP2, displaying DPP4-like activity. In contrast, DPP6 and DPP10 lack enzymatic DPP4-like activity. These DASH proteins play important roles in the immune system involving quiescence (DPP2), proliferation (DPP8/DPP9), antigen-presenting (DPP9), costimulation (DPP4), T cell activation (DPP4), signal transduction (DPP4, DPP8 and DPP9), differentiation (DPP4, DPP8) and tissue remodelling (DPP4, FAP). Thus, they are involved in many pathophysiological processes and have therefore been proposed for potential biomarkers or even drug targets in various cancers (DPP4 and FAP) and inflammatory diseases (DPP4, DPP8/DPP9). However, they also pose the challenge of drug selectivity concerning other DASH members for better efficacy and/or avoidance of unwanted side effects. Therefore, this review unravels the complex roles of DASH proteins in immunology.Keywords: antigen presentation/processing, CD26, co-stimulation, DPP4 activity and/or structure homologue proteins (DASH), signal transductionThe dipeptidyl peptidase (DPP)4 family of DPP4 activity and/or structure homologue (DASH) proteins Within the last two decades a number of enzymes have been discovered to also display DPP4-like activity or are structural homologues to DPP4. These enzymes/proteins are referred to as DPP4 activity and/or structure homologue (DASH) proteins, and can be grouped into the DPP4 gene family and non-related DPP4-like enzymes. Except for DPL1 and DPL2, all members display DPP4-like activity with neutral to basic pH optima and similar inhibition profiles [6,7]. DPP4 (CD26). DPP4 (CD26) is the best-known DASH protein and has been described in detail elsewhere [7][8][9].

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“…It has been shown that QPP inhibitors cause apoptosis in quiescent lymphocytes, but not in activated or transformed lymphocytes. This process is believed to be independent of DPP IV, because both DPP IV(+) and DPP IV(-) T cells undergo apoptosis [59][60][61][62][63]. This effect has been questioned later, since it has been shown that the QPP inhibitor (ValboroPro) used in these experiments, is also a potent inhibitor of FAP, DPP8 and DPP9 [18].…”

Section: Dipeptidyl Peptidase II (Dpp Ii)mentioning

confidence: 98%

Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

Veken

Haemers²,

Augustyns³

2007

CTMC

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Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of type 2 diabetes, with several inhibitors currently in phase 3 clinical trials. This review will mainly focus on proline-specific dipeptidyl peptidases related to DPP IV: fibroblast activation protein (FAP), dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase II (DPP II). The biochemical and biological properties of these enzymes will be discussed, as well as the therapeutic potential of their inhibition. The development of potent and selective inhibitors for each of these peptidases will be described.

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Homodimerization via a Leucine Zipper Motif is Required for Enzymatic Activity of Quiescent cell Proline Dipeptidase

Cited by 15 publications

References 24 publications

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

Structures of Human DPP7 Reveal the Molecular Basis of Specific Inhibition and the Architectural Diversity of Proline-Specific Peptidases

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

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