Structural Basis for Enzymatic Evolution from a Dedicated ADP-ribosyl Cyclase to a Multifunctional NAD Hydrolase

Liu, Qun; Graeff, Richard; Kriksunov, I.A.; Jiang, Hong; Zhang, Bo; Oppenheimer, Norman J.; Lin, Hening; Potter, Barry V. L.; Lee, Hon Cheung; Hao, Quan

doi:10.1074/jbc.m109.031005

Cited by 57 publications

(67 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The nicotinamide group of the substrate was released, and the ribose unit formed close association with the catalytic residue, Glu-179, of the cyclase (22). The close proximity suggests a covalent linkage, as we have previously shown for CD38 (35), although the resolution of the structure of the complex (3.0 Å) does not permit a definitive determination of the nature of the linkage in cyclase.…”

Section: Resultsmentioning

confidence: 77%

See 1 more Smart Citation

Mechanism of Cyclizing NAD to Cyclic ADP-ribose by ADP-ribosyl Cyclase and CD38

Graeff

Liu

Kriksunov

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Mammalian CD38 and its Aplysia homolog, ADP-ribosyl cyclase (cyclase), are two prominent enzymes that catalyze the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a Ca 2؉ messenger molecule responsible for regulating a wide range of cellular functions. Although both use NAD as a substrate, the cyclase produces cADPR, whereas CD38 produces mainly ADPribose (ADPR). To elucidate the catalytic differences and the mechanism of cyclizing NAD, the crystal structure of a stable complex of the cyclase with an NAD analog, ribosyl-2F-2de-oxynicotinamide adenine dinucleotide (ribo-2-F-NAD), was determined. The results show that the analog was a substrate of the cyclase and that during the reaction, the nicotinamide group was released and a stable intermediate was formed. The terminal ribosyl unit at one end of the intermediate formed a close linkage with the catalytic residue (Glu-179), whereas the adenine ring at the other end stacked closely with Phe-174, suggesting that the latter residue is likely to be responsible for folding the linear substrate so that the two ends can be cyclized. Mutating Phe-174 indeed reduced cADPR production but enhanced ADPR production, converting the cyclase to be more CD38-like. Changing the equivalent residue in CD38, Thr-221 to Phe, correspondingly enhanced cADPR production, and the double mutation, Thr-221 to Phe and Glu-146 to Ala, effectively converted CD38 to a cyclase. This study provides the first detailed evidence of the cyclization process and demonstrates the feasibility of engineering the reactivity of the enzymes by mutation, setting the stage for the development of tools to manipulate cADPR metabolism in vivo.Cyclic ADP-ribose is a novel cyclic nucleotide with Ca 2ϩ -mobilizing activity targeting the endoplasmic reticulum. Its activity was first described in sea urchin eggs (1, 2), and cADPR 3 has since been established as a second messenger molecule responsible for regulating a wide range of physiological functions, from fission in the dinoflagellate (3) to social behavior in mice (Ref. 4 and reviewed in Refs. 5 and 6). The Aplysia ADPribosyl cyclase (cyclase) was the first protein identified that uses NAD, a linear substrate, and ligates its two ends to produce cADPR, with the release of the terminal moiety, nicotinamide (7). The cyclase is a soluble protein of 30 kDa and is present in large amounts in Aplysia ovotestis (7). It is also present in the neurons of the Aplysia buccal ganglion, where it is responsible for the synthesis of endogenous cADPR and the regulation of the evoked synaptic transmission (8). Recently, it is shown that depolarization of Aplysia neurons induces the translocation of the cyclase from the cytosol into the nucleus, providing a mechanism for fine tuning of nuclear Ca 2ϩ signals in neurons (9). CD38 is the major mammalian homolog of the cyclase and is responsible for regulating a wide range of physiological functions. Deletion of the CD38 gene in mice produces multiple defects, including impairment of insulin secretion (10), neutrophil chemota...

show abstract

Section: Resultsmentioning

confidence: 77%

“…1a), for this purpose. We have previously shown that ribo-2ЈF-NAD and its isomer ara-2ЈF-NAD both form covalent intermediates with CD38 (35). Both analogs were tested with the cyclase, and only ribo-2ЈF-NAD, but not ara-2ЈF-NAD, was found to form a stable complex after infusing the analog into preformed cyclase crystals.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Cyclizing NAD to Cyclic ADP-ribose by ADP-ribosyl Cyclase and CD38

Graeff

Liu

Kriksunov

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, CD38 can also hydrolyze NAADP to ADP-ribose phosphate (73), whereas both enzymes can hydrolyze cADPR to ADP-ribose as well (Fig. 2, inset) (63,74). It thus appears that CD38 is specifically equipped to metabolize these two novel Ca 2ϩ messengers.…”

Section: Catalytic Mechanisms Of Cd38 and The Cyclasementioning

confidence: 99%

“…Using crystallography in combination with site-directed mutagenesis, the mechanism of this novel multicatalytic property of CD38 and the cyclase has been well elucidated (74 -78). It has been shown that NAD enters the active site pocket with the nicotinamide end first (74,76). The adenine end is extended out of the site and has high degree of freedom to move and rotate.…”

Section: Catalytic Mechanisms Of Cd38 and The Cyclasementioning

confidence: 99%

Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) as Messengers for Calcium Mobilization

Lee

2012

Journal of Biological Chemistry

Self Cite

176

178

View full text Add to dashboard Cite

Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate were discovered >2 decades ago. That they are second messengers for mobilizing Ca 2؉ stores has since been firmly established. Separate stores and distinct Ca 2؉ channels are targeted, with cyclic ADP-ribose acting on the ryanodine receptors in the endoplasmic reticulum, whereas nicotinic acid adenine dinucleotide phosphate mobilizes the endolysosomes via the two-pore channels. Despite the structural and functional differences, both messengers are synthesized by a ubiquitous enzyme, CD38, whose crystal structure and catalytic mechanism have now been well elucidated. How this novel signaling enzyme is regulated remains largely unknown and is the focus of this minireview.

show abstract

“…The human molecule conserves the ability to produce cADPR, even if at very low levels. 38 cADPR is a ubiquitous second messenger in eukaryotic cells. Smooth muscle cells of different origins (vascular, bronchial, and uterine), [39][40][41] along with epithelial and secretory cells (pancreas, kidney, and hypophysis the most studied), 42 are the best examples.…”

Section: Cd38 and Cll 3471mentioning

confidence: 99%

CD38 and chronic lymphocytic leukemia: a decade later

Malavasi

Deaglio

Damle

et al. 2011

Blood

193

160

View full text Add to dashboard Cite

This review highlights a decade of investigations into the role of CD38 in CLL. CD38 is accepted as a dependable marker of unfavorable prognosis and as an indicator of activation and proliferation of cells when tested. Leukemic clones with higher numbers of CD38 ؉ cells are more responsive to BCR signaling and are characterized by enhanced migration. In vitro activation through CD38 drives CLL proliferation and chemotaxis via a signaling pathway that includes ZAP-70 and ERK1/2. Finally, CD38 is under a polymorphic transcriptional control after external signals.Consequently, CD38 appears to be a global molecular bridge to the environment, promoting survival/proliferation over apoptosis. Together, this evidence contributes to the current view of CLL as a chronic disease in which the host's microenvironment promotes leukemic cell growth and also controls the sequential acquisition and accumulation of genetic alterations. This view relies on the existence of a set of surface molecules, including CD38, which support proliferation and survival of B cells on their way to and after neoplastic transformation. The second decade of studies on CD38 in CLL will tell if the molecule is an effective target for antibody-mediated therapy in this currently incurable leukemia. (Blood. 2011;118(13):3470-3478)The current view of chronic lymphocytic leukemia (CLL) is that of a disease characterized by a dynamic balance between cells circulating in the blood and cells located in permissive niches in lymphoid organs. 1 The former are primarily mature-looking small lymphocytes resistant to apoptosis, whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment. 2 The heterogeneous clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genomic alterations. 3 Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. [4][5][6][7] Cell surface CD38 is one of these markers.This review highlights a decade of investigations into the role of CD38 in CLL. An association between CD38 expression by CLL cells and a more aggressive clinical behavior was first reported in 1999 4 and confirmed by several subsequent studies. [8][9][10][11][12] Consequently, determination of the percentage of CD38-expressing cells within a clone has become part of the workup of CLL patients in many clinical centers, 13 and it is generally accepted that CD38 ϩ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner. 4 The underlying question behind these clinical observations is why expression of this molecule on the cell surface would correlate with a worse clinical outcome. The most obvious possibility is that CD38 expression reflects events occurring in...

show abstract

Structural Basis for Enzymatic Evolution from a Dedicated ADP-ribosyl Cyclase to a Multifunctional NAD Hydrolase

Cited by 57 publications

References 31 publications

Mechanism of Cyclizing NAD to Cyclic ADP-ribose by ADP-ribosyl Cyclase and CD38

Mechanism of Cyclizing NAD to Cyclic ADP-ribose by ADP-ribosyl Cyclase and CD38

Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) as Messengers for Calcium Mobilization

CD38 and chronic lymphocytic leukemia: a decade later

Contact Info

Product

Resources

About