Crystal structure of Aplysia ADP ribosyl cyclase, a homologue of the bifunctional ectozyme CD38

Gs, Prasad; De, McRee; Stura, E.A.; Levitt, DG; Hc, Lee; Cd, Stout

doi:10.1038/nsb1196-957

Cited by 143 publications

(146 citation statements)

References 54 publications

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“…The superfamily of ADP-ribosyl cyclases includes two mammalian members (CD38 and CD157) and a cyclase from the invertebrate Aplysia (sea slug) species (42,50). The primary amino acid sequence and the partial crystal structure of these three major ADP-ribosyl cyclases have been resolved (51)(52)(53). Analysis of the sequence and structural data indicates that the mammalian and invertebrate ADP-ribosyl cyclases have 25 to 30% identity in their primary structure (54,55).…”

Section: Adp-ribosyl Cyclase Cd38 and Cyclic Adp-ribose In Airway Smentioning

confidence: 99%

Calcium Signaling in Airway Smooth Muscle

Jude¹,

Wylam²,

Walseth³

et al. 2008

Proceedings of the American Thoracic Society

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Contractility of airway smooth muscle requires elevation of intracellular calcium concentration. Under resting conditions, airway smooth muscle cells maintain a relatively low intracellular calcium concentration, and activation of the surface receptors by contractile agonists results in an elevation of intracellular calcium, culminating in contraction of the cell. The pattern of elevation of intracellular calcium brought about by agonists is a dynamic process and involves the coordinated activities of ion channels located in the plasma membrane and the sarcoplasmic reticulum. Among the signaling molecules involved in this dynamic calcium regulation in airway smooth muscle cells are inositol 1,4,5-trisphosphate and cyclic ADPribose, which mobilize calcium from the sarcoplasmic reticulum by acting via the inositol 1,4,5-trisphosphate and ryanodine receptors, respectively. In addition, calcium influx from the extracellular space is critical for the repletion of the intracellular calcium stores during activation of the cells by agonists. Calcium influx can occur via voltage-and receptor-gated channels in the plasma membrane, as well as by influx that is triggered by depletion of the intracellular stores (i.e., store-operated calcium entry mechanism). Transient receptor potential proteins appear to mediate the calcium influx via receptor-and store-operated channels. Recent studies have shown that proinflammatory cytokines regulate the expression and activity of the pathways involved in intracellular calcium regulation, thereby contributing to airway smooth muscle cell hyperresponsiveness. In this review, we will discuss the specific roles of cyclic ADP-ribose/ryanodine receptor channels and transient receptor potential channels in the regulation of intracellular calcium in airway smooth muscle cells. DYNAMIC INTRACELLULAR CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE CELLSExposure of airway smooth muscle (ASM) cells to contractile agonists results in a biphasic elevation of intracellular calcium concentration ([Ca 21 ] i ) that is characterized by an initial rapid and transient rise in calcium, followed by a decline to a lower, sustained steady-state concentration above the basal level (1-3). This biphasic [Ca 21 ] i response results from calcium influx from the extracellular space and release of calcium from the intracellular stores (i.e., the sarcoplasmic reticulum [SR]). Earlier studies have attributed the initial rapid and transient phase of the [Ca 21 ] i response to release from the SR, while the sustained phase of the response was thought to be due to influx from the extracellular space (2-6). Recent investigations using the improved temporal and spatial resolution features of real-time confocal microscopy have shed light on the dynamics of the [Ca 21 ] i response in ASM cells. These studies have shown that the biphasic [Ca 21 ] i response of ASM cells elicited by contractile agonists in reality consists of propagating regenerative calcium oscillations that originate at a location within a cell and propagate...

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Section: Adp-ribosyl Cyclase Cd38 and Cyclic Adp-ribose In Airway Smentioning

confidence: 99%

Calcium Signaling in Airway Smooth Muscle

Jude¹,

Wylam²,

Walseth³

et al. 2008

Proceedings of the American Thoracic Society

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“…While CD38 is a membrane-bound ectoenzyme, the invertebrate ADP-ribosyl cyclase is a cytoplasmic, soluble enzyme [6]. The ectocellular localization of CD38 in vertebrates raises *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Dimeric and tetrameric forms of catalytically active transmembrane CD38 in transfected HeLa cells

et al. 1998

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CD38, a type II transmembrane glycoprotein, behaves as a catalytically active transporter responsible for ectocellular generation of cyclic ADP-ribose (cADPR) from NAD + and for subsequent influx of cADPR across membranes [Franco, L., Guida, L., Bruzzone, S., Zocchi, E., Usai, C. and De Flora, A. (1998) FASEB J. in pressJ, cADPR regulates intracellular calcium homeostasis by releasing calcium from responsive stores. The cADPR-transporting function of CD38 requires channel-generating oligomeric forms of the protein rather than the 46 kDa monomers that have been described so far in CD38 + cells. Here we demonstrate that CD38, both in reconstituted proteoliposomes and in CD38-transfected HeLa cells, is a mixture of catalytically active monomers, homodimers and homotetramers. A soluble recombinant form of CD38 corresponding to its ectocellular region proved to be monomeric. Thus, association of native CD38 with either artificial or natural membranes seems to result in a reversible juxtaposition of monomers suitable to cADPR-transporting activity.

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“…Although the exact mechanism by which reducing power induces CD38 internalization is yet to be determined, one of the explanations would be that reduction of the cysteine 119-cysteine 201 disulfide bond in a CD38 molecule would favor formation of the intermolecular disulfide bond between different CD38 molecules, producing dimerization (or oligomerization) of CD38 (21). Receptor dimerization (or oligomerization) has been well established to be prerequisite for subsequent internalization (25), Alternatively, breakage of the disulfide bond between cysteine 119 and cysteine 201 itself may result in a conformational change of CD38 to induce its internalization, as predicted previously from the data of the crystal structure of Aplysia cyclase (16).…”

Section: Discussionmentioning

confidence: 93%

“…Aplysia cyclase was cloned and recombinantly expressed, and its three-dimensional structure was determined (16). The three-dimensional picture predicts that the amino acid residues corresponding to cysteine 119 and cysteine 201 of human CD38 are located on the outer surface of the enzyme, linked by a disulfide bond.…”

Section: Discussionmentioning

confidence: 99%

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Antidiabetic Effect of a Prodrug of Cysteine,l-2-Oxothiazolidine-4-carboxylic Acid, through CD38 Dimerization and Internalization

Han¹,

Kim²,

Park³

et al. 2002

Journal of Biological Chemistry

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CD38 is a bifunctional enzyme synthesizing (ADP-ribosyl cyclase) and degrading (cyclic ADP-ribose (cADPR) hydrolase) cADPR, a potent Ca 2؉ mobilizer from intracellular pools. CD38 internalization has been proposed as a mechanism by which the ectoenzyme produced intracellular cADPR, and thiol compounds have been shown to induce the internalization of CD38. Here, we show that the disulfide bond between Cys-119 and Cys-201 in CD38 may be involved in CD38 dimerization and internalization. We tested the effect of a reducing agent, L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, on CD38 internalization in pancreatic islets. OTC enhanced insulin release from isolated islets as well as CD38 internalization and cytoplasmic Ca 2؉ level. Furthermore, islet cells treated with antisense CD38 oligonucleotide showed inhibition of OTCinduced insulin secretion. Intake of OTC in db/db mice ameliorated glucose tolerance, insulin secretion, and morphology of islets when compared with control mice. These data indicate that OTC improves glucose tolerance by enhancing insulin secretion via CD38/cADPR/ Ca 2؉ signaling machinery. Thus, OTC may represent a novel class of antidiabetic drug.

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Crystal structure of Aplysia ADP ribosyl cyclase, a homologue of the bifunctional ectozyme CD38

Cited by 143 publications

References 54 publications

Calcium Signaling in Airway Smooth Muscle

Calcium Signaling in Airway Smooth Muscle

Dimeric and tetrameric forms of catalytically active transmembrane CD38 in transfected HeLa cells

Antidiabetic Effect of a Prodrug of Cysteine,l-2-Oxothiazolidine-4-carboxylic Acid, through CD38 Dimerization and Internalization

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