Identification of Regulatory Domains in ADP-ribosyltransferase-1 That Determine Transferase and NAD Glycohydrolase Activities*
Christelle Bourgeois
,
Ian Okazaki,
Eleanor Cavanaugh,
Maria Nightingale and
Joel Moss
From the
Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of
Health, Bethesda, Maryland 20892-1590
Received for publication, March 28, 2003
, and in revised form, April 24, 2003.
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ABSTRACT
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Mono-ADP-ribosyltransferases (ART17) transfer ADP-ribose from
NAD+ to proteins (transferase activity) or water (NAD
glycohydrolase activity). The mature proteins contain two domains, an
-helical amino terminus and a
-sheet-rich carboxyl terminus. A
basic region in the carboxyl termini is encoded in a separate exon in ART1 and
ART5. Structural motifs are conserved among ART molecules. Successive amino-
or carboxyl-terminal truncations of ART1, an arginine-specific transferase,
identified regions that regulated transferase and NAD glycohydrolase
activities. In mouse ART1, amino acids 2438 (ART-specific extension)
were needed to inhibit both activities; amino acids 3945 (common ART
coil) were required for both. Successive truncations of the
-helical
region reduced transferase and NAD glycohydrolase activities; however,
truncation to residue 106 enhanced both. Removal of the carboxyl-terminal
basic domain decreased transferase, but enhanced NAD glycohydrolase, activity.
Thus, amino- and carboxyl-terminal regions of ART1 are required for
transferase activity. The enhanced glycohydrolase activity of the shorter
mutants indicates that sequences, which are not part of the NAD binding, core
catalytic site, exert structural constraints, modulating substrate specificity
and catalytic activity. These functional domains, defined by discrete exons or
structural motifs, are found in ART1 and other ARTs, consistent with
conservation of structure and function across the ART family.
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INTRODUCTION
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Post-translational modification of proteins by mono- or
poly-(ADP-ribosylation) has been implicated in the regulation of a variety of
biological processes (e.g., T-cell activation, cytoskeleton
reorganization, apoptosis). In several systems, the effect on function could
be reversed by removal of the ADP-ribose moiety by ADP-ribosylprotein
hydrolases or lyases, consistent with the existence of
ADP-ribosylation/de-ADP-ribosylation cycles. In the case of
mono-ADP-ribosyltransferases
(ARTs),1 a single
ADP-ribose (ADPR) moiety from NAD is transferred to a specific amino acid in a
target protein. In addition to using proteins or amino acids as acceptors,
most of these enzymes can also transfer ADP-ribose to water. The latter
activity results in NAD hydrolysis (NAD glycohydrolase (NADase) activity)
(1).
Mono-ADP-ribosylation was first recognized as the mode of action of
diphtheria toxin, cholera toxin, and other bacterial toxins
(2). Subsequently, vertebrate
mono-ADP-ribosyltransferases, sharing structural homology with prokaryotic
toxin counterparts, were identified. To date, the family of known vertebrate
ARTs consists of seven members (ART17); all appear to be
glycosylphosphatidylinositol (GPI)-anchored or secreted proteins
(1,
3). Although they share less
than 10% similarity at the level of amino acid sequence, there are several
common structural features that define the family: four conserved cysteines, a
consensus "ART signature" sequence, an
-helix-rich
amino-terminal region, and a carboxyl-terminal region folded into
-sheets. The latter, by analogy to the structural organization of
bacterial ADP-ribosylating enzymes, forms their NAD-binding and catalytic
sites (4). The mammalian
art genes have exons encompassing signal sequences for ER transfer
(amino terminus) and addition of the GPI-anchor (carboxyl terminus). The
region responsible for catalysis is found in one exon. In some ARTs, however,
a basic region is encoded by a separate exon at the carboxyl-terminal end of
the coding region (1,
3). Thus, in general, across
ART family members, different exons encode functional regions of the protein;
within the coding region exon, different structural motifs may be responsible
for function.
ART1, the first cloned and characterized vertebrate ART, is an
arginine-specific ADP-ribosyltransferase
(3,
58)
that is relatively conserved across species with deduced amino acid sequence
of the mouse protein 77 and 73% identical to those of the human and rabbit,
respectively (9). This
cell-surface, GPI-anchored protein modifies integrin
7 in
mouse skeletal muscle cells
(10). An increase in
arginine-specific ADP-ribosylation was observed during the process of
differentiation into myotubes
(11,
12). In vitro, ART1
ADP-ribosylates human defensin-1, leading to changes in its biological
properties; ADP-ribosylated human defensins were also detected in
vivo, consistent with a modulatory role for mono-ADP-ribosylation in
innate immunity (13). In a
T-cell lymphoma line stably transfected with ART1, the function of the TCR was
altered in the presence of NAD through modification of LFA-1 and other
co-receptor proteins (14).
Structure/function studies of ART isoforms have thus far focused on the
-sheet-rich domain of the protein and characterization of the catalytic
regions. In rabbit ART1, glutamate (Glu-240) was identified as the catalytic
amino acid, and even the conservative E240D substitution abolished ADP-ribose
transfer to arginine. Nearby Glu-238 was also critical for ADP-ribose transfer
(15). In several ARTs,
replacement of this Glu altered the ability of the transferases to use
arginine or other guanidino compounds as acceptors, supporting the hypothesis
that this region is involved in acceptor recognition
(16).
Little is known about the role of the
-helical region of the protein
in ART activity. The fact that the carboxyl-terminal basic region is a
separate exon raised the possibility that it could play a role in regulating
catalytic actions. Since motifs appear to be responsible for function and
targeting elsewhere in ART enzymes, we hypothesized that within the coding
region, these motifs may regulate activity. By using truncated mutants of ART1
protein, we identified amino- and carboxyl-terminal regions that influence
ART1 catalytic activity. Based on these data, it appears that conserved motifs
within the amino- and carboxyl-terminal regions increase the specificity of
the catalysis by exerting some constraints on the active site.
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MATERIALS AND METHODS
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FLAG-tagged Deletion Mutants of ART1Several truncated forms
of mART1 were generated by PCR amplification
(17) using the forward (F) and
reverse (R) primers listed in Table
I. PCR products were subcloned into the procaryotic expression
vector pFLAG-MAC (Sigma), using Hin-dIII and KpnI
restriction enzymes, and expressed in Escherichia coli (DH5
,
Invitrogen). Plasmid sequences were verified by DNA sequencing of the entire
open reading frame. The amino-terminal FLAG-tagged recombinant proteins were
purified from bacterial lysates using M2 affinity chromatography according to
the manufacturer's instructions (Sigma), and enzymatic activity was
measured.
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TABLE I PCR primers used to generate the truncated ART1 mutants
Underlined are the HindIII and KpnI restriction site
sequences used for subcloning. F, forward primer; R, Reverse primer; m, mouse;
r, rabbit.
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NAD Glycohydrolase and ADP-ribosyltransferase
AssaysNicotinamide release (standard assay) was measured with
(ADP-ribosyltransferase activity) or without (NAD glycohydrolase activity) 20
mM agmatine, in Dulbecco's phosphate-buffered saline containing 7
µM [carbonyl-14C]NAD (0.05 µCi/assay,
Amersham Biosciences) at 30 °C for the indicated time (total volume, 300
µl). Samples (100 µl) were applied to columns (0.4 x 4 cm) of
AG1-X2 (Bio-Rad), equilibrated, and eluted with water for radioassay of
[14C]nicotinamide
(18). Transferase activity was
assayed similarly with or without 20 mM agmatine as an ADP-ribose
acceptor and with [adenine-14C]NAD substituted for
[carbonyl-14C]NAD so that
[adenine-14C]ADP-ribose-agmatine would be generated.
Activity was normalized to the amount of recombinant protein present in each
preparation by densitometric analysis of Coomassie Blue-stained gels (see
under "Quantification of Truncated Mutants").
[32P]ADP-ribosylation of
ProteinsAffinity-purified recombinant proteins (1 µg) were
incubated in Dulbecco's phosphate-buffered saline with 5 µM
[32P]NAD (10 µCi/reaction, Amersham Biosciences) and 1
mM ADP-ribose (to dilute out the effects of non-enzymatic addition
of [32P]ADP-ribose on the autoradiogram), in a final volume of 100
µl, for 1 h at 30 °C. The reaction was stopped with 100 µl of 20%
cold trichloroacetic acid. Reaction mixtures were centrifuged (16,000 x
g, 30 min) and supernatants discarded. Proteins were dissolved in
SDS-sample buffer, separated by SDS-PAGE in 1020% gradient gels, and
transferred to nitrocellulose. Blots were exposed to x-ray film (XAR-2,
Eastman Kodak Co.).
Quantification of Truncated MutantsAffinity-purified mutant
proteins together with 10-ng to 4-µg amounts of SDS-PAGE low molecular
weight standards (Bio-Rad) were separated by SDS-PAGE in 1020% gradient
gels. After Coomassie Blue staining of the gels, optical density measurement
of the bands (Epson scanner, Scion densitometry software) produced a standard
curve, which was used to calculate the concentration of each truncated mutant
protein.
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RESULTS AND DISCUSSION
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Structure/function studies of mammalian ARTs have, thus far, focused on the
carboxyl-terminal half of the molecules, a predicted
-sheet-rich region
which, based on crystallographic structure of the bacterial toxins
(1926)
and rat ART2 (27), contains
the catalytic site. Its secondary structure is analogous to that of the active
site of prokaryotic ARTs (4);
it is formed by the interaction of three regions (I, II, and III). Regions I
and II, involved in stabilizing the NAD binding, are defined, respectively, by
a conserved arginine and a consensus "serine X serine"
motif (where X is any amino acid). Region III contains the catalytic
glutamate required for NAD hydrolysis. A basic region, located at the
carboxyl-terminal end of the
-sheet-rich region, is, in some ARTs,
encoded in a separate exon (amino acids 277290 in mART1)
(1,
3). The amino-terminal region
of ART proteins, by contrast, is predicted to contain
-helices, the
function(s) of which has not been determined. To investigate the functions of
the conserved domains within the amino- and carboxyl-terminal regions adjacent
to the catalytic core of the ARTs, we monitored transferase and NADase
activities of ART1 mutants generated by progressive deletions from the amino
or carboxyl termini of the protein (Fig.
1 and Fig.
5B, respectively).

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FIG. 1. Structures of mouse ART1 amino-terminal deletion mutants. Residues
at the amino and carboxyl termini of the molecules are numbered, and
exon/intron junctions are marked by separations. Residues
277290 are encoded by a short exon of the mART1 gene. Enzyme
catalytic core and characteristics of deleted regions are shown by
different shadings. Nt and Ct, amino and carboxyl termini. Not drawn
to scale.
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FIG. 5. A, amino acid sequences of the small basic domain adjacent to the
catalytic site in mouse and rabbit ART. Amino acid charge is indicated by +
and . Net charge for each basic region is on the right. B,
structures of mouse and rabbit ART1 carboxyl-terminal deletion mutants.
Residues at the amino and carboxyl termini (Nt and Ct) of
the molecules are numbered, and the exon/intron junctions are marked
by separations. Residues 277290 in mART1 and residues
282295 in rART1 are encoded by a short exon of the respective genes.
Enzyme catalytic core and characteristics of deleted regions are shown by
different shadings. Rabbit ART1 putative exon/intron junctions were
drawn by comparison with the gene structure of mouse ART1 as rabbit
art1 gene structure is not known. Not drawn to scale.
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Regions Surrounding the NAD-binding Catalytic Core Suppress NAD
Hydrolysis and Enhance ADP-ribose Transfer to AcceptorIn
mART1-(24288) and rART1-(24293) mutants, signal sequences
necessary for export from the ER (at the amino terminus) and addition of a
GPI-anchor (at the carboxyl terminus) were deleted. The resulting mutants
retained the catalytic properties of the mature wild-type ART1. Their NADase
activities relative to transferase activities were very low, and nicotinamide
release was enhanced in the presence of the ADP-ribose acceptor, agmatine,
reflecting, as expected, a preference for a guanidino moiety over water as an
ADP-ribose acceptor (Fig. 2 and
Fig. 6). The products of the
reaction were hydrolyzed by the stereo-specific ADP-ribosylarginine hydrolase,
consistent with the formation of the
-anomer. These results are
consistent with ART1 being primarily an arginine-specific
ADP-ribosyltransferase that employs an Sn2-like mechanism
in the formation of
-ADP-ribose-agmatine from
-NAD. Amino acids
2438 correspond to an amino-terminal extension in the GPI-anchored ART1
transferase, which is slightly longer than those in other NADases and/or
arginine-specific ADP-ribosyltransferases of the ART family and relatively
conserved across species (Fig.
3) (9). On the
contrary, region 3945 is similar among these isoforms
(Fig. 3), and comparison of its
predicted secondary structure with rat ART2 crystal structure
(27) suggests that these amino
acids form a coil just amino-terminal to a long
-helical region that is
conserved among ART isoforms. Deletion of residues 2438 of mART1
enhanced NAD hydrolysis as well as ADP-ribose transfer to agmatine. Further
amino-terminal deletions of residues 3945 resulted in a decrease of
transferase activities but not of NADase activity when compared with
ART1-(24288) activities. Measurement of ADP-ribose-agmatine formation
confirmed the inhibitory influence of amino acids 2438 on ADP-ribose
transfer (data not shown); additional deletions from the amino terminus
completely abolished transferase activity
(Fig. 4). These results suggest
that ART1-specific amino acids 2438 are inhibitory for both enzymatic
activities, whereas ART-conserved amino acids 3945 are necessary for
proper transfer of ADP-ribose to agmatine but do not affect NADase activity.
Thus, the ART1-specific extension and the ART-common structural motif appear
to have different functional effects on ART activity.

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FIG. 2. Nicotinamide release catalyzed by mouse ART1 amino-terminal deletion
mutants measured with or without agmatine. Affinity-purified mutant
proteins were incubated for 14 h at 30 °C with 7 µM
[carbonyl-14C]NAD and 1 mM ADP-ribose, with
(+Ag) or without (Ag) 20 mM agmatine
(final volume, 300 µl), before quantification of nicotinamide release and
calculation of release per mg of each mutant protein. Similar results were
obtained using 14.5 µM NAD. Data presented are from one
experiment representative of results obtained with two different protein
purifications. Each activity measurement was performed in duplicate.
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FIG. 6. Nicotinamide release catalyzed by mouse and rabbit ART1
carboxyl-terminal deletion mutants measured without or with agmatine.
Affinity-purified mutant proteins were incubated for 14 h at 30 °C with 7
µM [carbonyl-14C]NAD and 1 mM
ADP-ribose, with (+Ag) or without (Ag) 20
mM agmatine, (final volume, 300 µl), before quantification of
nicotinamide release and calculation of release per mg of mutant protein in
each preparation. Similar results were obtained using 14.5 µM
NAD. Data presented are from one experiment representative of results obtained
with two different protein purifications. Each activity measurement was
performed in duplicate.
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FIG. 3. Alignment of amino-terminal regions of ART1, -2, and -5 isoforms.
Deduced amino acid sequences of human, mouse (m), and rabbit
(rab) ART1, mouse (m) and rat ART2A and ART2B, and mouse
ART5 were aligned using Clustal (Gene Works). Highly conserved regions are
boxed and shaded (cost=0) or shaded only (cost
1), based on the method of Higgins and Sharp
(28) as utilized by the
Clustal program. The conserved cysteine involved in disulfide bridge formation
in the rat ART2B protein (27)
is marked by *. Positions of the mART1 amino-terminal deletions are indicated
at top.
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FIG. 4. Synthesis of ADP-ribose-agmatine by mouse ART1 amino-terminal deletion
mutants. Affinity-purified mutant proteins were incubated for 4 h at 30
°C with 7 µM [adenine-14C]NAD, 1
mM ADP-ribose, and 20 mM agmatine (final volume, 300
µl). ADP-ribose-agmatine was separated by anion exchange chromatography and
quantified by scintillation counting. Data are expressed as nicotinamide
released per mg of mutant protein in each preparation. Similar results were
obtained using 100 µM NAD. Data presented are from one
experiment representative of results obtained with two different protein
purifications. Each activity measurement was performed in duplicate.
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In contrast, region 67105 appears to be inhibitory for NADase
activity. The shortest mutant, mART1-(106288), was primarily an NADase,
consistent with the lack of transferase activity of the core fragment (Figs.
3 and
4). Residues 52105
include a cysteine (Cys-53 in mART1) conserved among all isoforms
(Fig. 3). According to the rat
ART2.2 crystal structure (27),
Cys-53 is predicted to form a disulfide bond with another conserved cysteine
(Cys-272) at the carboxyl terminus of the molecule, which stabilizes folding
of the
-helix-rich domain. This region appears not to be required for
NAD hydrolysis.
Effect of the Basic Region Encoded by the Small ExonART1
proteins contain a short basic region at the end of the catalytic core
(Fig. 5A) that is
encoded by a small exon, found also in the art5 gene, but not in the
art2 or art4 genes. In ART1 proteins, the amino acid stretch
encoded by this exon is rather conserved across species. In the ART family,
exons appear to encode functional domains (amino-terminal signal sequence for
ER transfer, carboxyl-terminal signal sequence for addition of the GPI
anchor). Therefore, we investigated if this exon as well encodes a motif with
functional effects on catalytic activity. To determine the influence of this
basic region on ART1 enzyme activity, mutants were generated by deletion from
the carboxyl terminus of mouse ART1 (Fig.
5B). Since the equivalent region in rabbit ART1 differs
in pI (Fig. 5A), ART1
rabbit deletion mutants were also generated for comparison. In both
mART1-(24276) and rART1-(24281), deletion of the small
carboxyl-terminal basic region increased NAD hydrolysis. NADase activity of
mART1-(24265) was further enhanced by deletion of amino acids 276 to
266 (Fig. 6). In contrast,
nicotinamide release in the presence of agmatine was either not affected
significantly by the additional deletions from the carboxyl terminus
(mART1-(24276)) or was decreased (mART1-(24295) and
rART1-(24281)) (Figs. 6
and 7). Therefore,
carboxyl-terminal truncations resulted in an overall relative loss of
transferase activity, reflecting an increase in acceptor-independent
nicotinamide release. Region 266288 contains the highly conserved
Cys-272 (Fig. 5B).
Results obtained with the carboxyl-terminal truncations are in agreement with
the conclusion that in the amino-terminal truncated mutants, the predicted
disulfide-bridge between Cys-53 and Cys-272 appears important for ADP-ribose
transfer but not for NAD+ hydrolysis.

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FIG. 7. Synthesis of ADP-ribose-agmatine by mouse and rabbit ART1
carboxyl-terminal deletion mutants. Affinity-purified mutant proteins were
incubated for 4 h at 30 °C with 7 µM
[adenine-14C]NAD, 1 mM ADP-ribose, and 20
mM agmatine (final volume, 300 µl). ADP-ribose-agmatine was
separated by anion exchange chromatography and quantified by scintillation
counting. Data are expressed as nicotinamide release per mg of mutant protein
in each preparation. Similar results were obtained using 100 µM
NAD. Data presented are from one experiment representative of results obtained
with two different protein purifications. Each activity measurement was
performed in duplicate.
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[32P]ADP-ribosylation of ProteinsTo assess
further the ability of the ART1 mutant proteins to transfer ADP-ribose to
acceptor proteins, recombinant mutant proteins were incubated with
32P-NAD+ and separated by SDS-PAGE
(Fig. 8). Mutants
mART1-(24288), mART1-(39288), and to a lesser extent
mART1-(24276) catalyzed the ADP-ribosylation of numerous proteins. The
transferase assay appears capable of identifying bands not readily seen in
Coomassie Blue-stained gels. Prior studies have shown that the availability of
arginine acceptors for ADP-ribose differs across proteins and increases with
denaturation of the
protein.2 Activities
of rabbit ART1 mutants were similar to those of their mouse counterparts. All
other deletion mutants lacked transferase activity. These results are
consistent with the agmatine-specific transferase activities determined for
each of these mutants (Figs. 4
and 7).

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FIG. 8. Protein ADP-ribosylation by mART1 and rART1 mutants.
Affinity-purified mutant proteins (1 µg) were incubated for1hat 30 °C
with 5 µM [32P]NAD (10 µCi) and 1 mM
ADP-ribose (final volume, 100 µl). After precipitation with 10%
trichloroacetic acid, proteins were dissolved in sample buffer, separated by
SDS-PAGE in 1020% gradient gels, and either stained with Coomassie Blue
(lower panel) or transferred to Immobilon P membrane that was exposed
to x-ray film for 17 h (upper panels). Data presented are from one
experiment representative of results obtained with two different protein
purifications.
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By functional characterization of ART1 molecules that were truncated from
the amino- and carboxyl-terminal ends, we identified several regions that
influence the transfer of ADP-ribose to an acceptor amino acid or to water. At
the amino terminus, an ART1-specific extension, amino acids 2438, and a
coil region common to ARTs, amino acids 3945, modulated both types of
transfer but with opposite effects; ART1-specific amino acids 2438 were
inhibitory, and ART-conserved residues 3945 necessary, for ADP-ribose
transfer. In contrast, residues 46106 were required for
ADP-ribose-agmatine formation, as were regions encoded by the small basic exon
specific of ART1 isoforms (amino acids 276288 in mART1 or 281293
in rART1) near the carboxyl terminus. Enhanced NADase activity of the shortest
deletion mutants suggests that the
-sheet-rich carboxyl-terminal domain
can maintain a structure adequate for catalysis of NAD hydrolysis independent
of the
-helix-rich region. Thus, the two structurally distinct domains
of ART1, the
-helix-rich amino terminus and the mainly
-sheet
carboxyl terminus, appear to contribute to different catalytic functions with
the catalytic core alone retaining NAD hydrolysis activity. The ART1-specific
and ART-conserved regions from amino-terminal
-helical and
carboxyl-terminal basic domains may modulate the catalytic activity of a
predominantly
-sheet catalytic core, in particular, its substrate
specificity. It may be relevant that in some ARTs, the carboxyl-terminal basic
domain is encoded in a separate exon. Our data suggest that this exon could
play a regulatory role in modulating substrate specificity.
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FOOTNOTES
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* The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section 1734
solely to indicate this fact. 
To whom correspondence should be addressed: Pulmonary-Critical Care Medicine
Branch, Bldg. 10, Rm. 6D05, NHLBI, National Institutes of Health, Bethesda, MD
20892-1590. Tel.: 301-496-4555; E-mail:
bourgeoc{at}nhlbi.nih.gov.
1 The abbreviations used are: ART, mono-ADP-ribosyltransferase; GPI,
glycosylphosphatidylinositol; NADase, NAD glycohydrolase; ADPR,
ADP-ribose. 
2 J. Moss, S. Stanley, and R. Levine, unpublished data. 
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ACKNOWLEDGMENTS
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We thank Dr. Martha Vaughan and Dr. Vincent Manganiello for useful
discussions and critical review of the manuscript.
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