Crystal Structure of CD26/Dipeptidyl-peptidase IV in Complex with Adenosine Deaminase Reveals a Highly Amphiphilic Interface

Weihofen, W.A.; Liu, Jiango; Reutter, Werner; Saenger, Wolfram; Fan, Hao

doi:10.1074/jbc.m405001200

Cited by 98 publications

(117 citation statements)

References 37 publications

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“…In DC, unlike in lymphocytes, ADA is very poorly colocalized with CD26. The crystal structure of the CD26-ADA complex (38) does not show in ADA two but just one motive capable of interacting with CD26. Then it is unlikely that ADA would bind two CD26 molecules, one expressed on the T cell surface and another on the DC surface.…”

Section: Resultsmentioning

confidence: 88%

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse

Pacheco

Martinez-Navío

Lejeune

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

221

192

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Adenosine deaminase (ADA), a protein whose deficit leads to severe combined immunodeficiency, binds to the cell surface by means of either CD26, A 1 adenosine receptors, or A2B adenosine receptors. The physiological role of these interactions is not well understood. Our results show that by a 3-fold reduction in the EC 50 for the antigen, ADA potentiated T cell proliferation in autologous cocultures with antigen-pulsed immature or mature dendritic cells. Costimulation was not due to the enzymatic activity but to the interaction of ADA-CD26 complexes in T cells with an ADAanchoring protein in dendritic cells. From colocalization studies, it is deduced that ADA colocalizing with adenosine receptors on dendritic cells interact with CD26 expressed on lymphocytes. This costimulatory signal in the immunological synapse leads to a marked increase (3-to 34-fold) in the production of the T helper 1 and proimmflamatory cytokines IFN-␥, TNF-␣, and IL-6. adenosine deaminase ͉ costimulation ͉ immunosynapse A denosine deaminase (ADA; EC 3.5.4.4) an enzyme involved in purine metabolism, catalyzes the hydrolytic deamination of adenosine or 2Ј-deoxyadenosine to inosine or 2Ј-deoxyinosine and ammonia. Congenital defect of ADA causes severe combined immunodeficiency, which is characterized by the absence of functional T and B lymphocytes in affected individuals (1). For many years, ADA was considered to be cytosolic, but it has been found on the cell surface of many cell types; therefore, it can be considered an ectoenzyme. In addition, ecto-ADA has been proposed to have a catalytic-independent function as a costimulatory molecule in lymphocytes (2).So far, two types of surface anchoring proteins for ecto-ADA have been described. The first type, with only one member, is CD26, a multifunctional protein of 110 KDa strongly expressed on epithelial cells (kidney proximal tubules, intestine, and bile duct) and on several types of endothelial cells and fibroblasts and on leukocyte subsets (3-5). The second type of ecto-ADA-binding proteins includes the adenosine receptors (AR) A 1 (A 1 R) (6) and A 2B (A 2B R) (7). The association between ADA and CD26 on the T cell surface has been proposed to have a costimulatory function during T cell antigen receptor-CD3 complex engagement (2). Because CD26 has a short cytoplasmatic tail, it needs partners to transduce the signal. Ishii et al. (8) have described that CD26-mediated signaling occurs through its association with CD45RO. At present, it is not known whether ADA generates a signal when it binds to AR. However, we have previously demonstrated that ADA binding to A 1 R or A 2B R is required for high efficiency affinity binding of the agonist and for efficient agonist-dependent signaling (6, 7).Dendritic cells (DC) are the most potent antigen-presenting cells (APC) specialized in the initiation of immune responses by directing the activation and differentiation of naïve T lymphocytes (9, 10). Immature DC (iDC) reside in most tissues to uptake antigen; they are engaged when exposed to danger ...

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Section: Resultsmentioning

confidence: 88%

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse

Pacheco

Martinez-Navío

Lejeune

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

221

192

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“…DPPIV is a multifunctional cell surface protein that, as well as having dipeptidase activity, is the major binding protein for adenosine deaminase and binds extracellular matrix proteins such as fibronectin and collagen. 16,27 This serine protease, aberrantly expressed in many cancers, functions as a tumor suppressor by regulating the activities of mitogenic peptides implied in cancer development and its decreased expression has been linked to increases in invasion and metastasis. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen whose signaling pathway can be blocked by DPPIV thus inhibiting the malignant phenotype of prostate cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Extracellular matrix degrading enzymes at the prostasome surface

Bellezza¹,

Aisa²,

Palazzo³

et al. 2005

Prostate Cancer Prostatic Dis

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Prostasomes, prostatic secretory vesicles found in human ejaculates, were analyzed to verify the existence at their surfaces of enzymes involved in the degradation of the extracellular matrix. Findings were compared with those of prostasomes isolated from two human adenocarcinoma cell lines that reflect clinical features and molecular pathways of androgen-insensitive and hormone-responsive prostate cancer. Our aim was to determine whether neoplastic transformation is accompanied by changes of glycosidase and protease activities. Our results show that decreases of dipeptidyl peptidase IV and increases of urokinase plasminogen activator and cathepsin B are consistent with the clinical features of the cell lines, whereas increases of glycosidase activities seem to be of scarce biological significance.

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“…Although it is likely that Saf1p interacts with Aah1p through the RCC1 like domain, the precise mode of interaction is not known. Interestingly, it has been found that bovine ADA, which shares homology with Aah1p, and human dipeptidyl peptidase IV ectodomain, which adopts an eight-bladed ␤-propeller fold, bind laterally through interaction between two helices of ADA and loops of two blades in the ␤-propeller (30).…”

Section: Discussionmentioning

confidence: 99%

Skp1-Cullin-F-box-dependent Degradation of Aah1p Requires Its Interaction with the F-box Protein Saf1p

Escusa

Laporte

Massoni

et al. 2007

Journal of Biological Chemistry

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When yeast cells enter into quiescence in response to nutrient limitation, the adenine deaminase Aah1p is specifically degraded via a process requiring the F-box protein Saf1p and components of the Skp1-Cullin-F-box complex. In this paper, we show that Saf1p interacts with both Aah1p and Skp1p. Interaction with Skp1p, but not with Aah1p, requires the F-box domain of Saf1p. Based on deletion and point mutations, we further demonstrate that the F-box domain of Saf1p is critical for degradation of Aah1p. We also establish that overexpression of Saf1p in proliferating cells is sufficient to trigger the degradation of Aah1p. Using this property and a two-dimensional protein gel approach, we found that Saf1p has a small number of direct targets. Finally, we isolated and characterized several point mutations in Aah1p, which increase its stability during quiescence. The majority of the mutated residues are located in two distinct exposed regions in the Aah1p three-dimensional model structure. Two hybrid experiments strongly suggest that these domains are directly involved in interaction with Saf1p.

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Crystal Structure of CD26/Dipeptidyl-peptidase IV in Complex with Adenosine Deaminase Reveals a Highly Amphiphilic Interface

Cited by 98 publications

References 37 publications

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse

Extracellular matrix degrading enzymes at the prostasome surface

Skp1-Cullin-F-box-dependent Degradation of Aah1p Requires Its Interaction with the F-box Protein Saf1p

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