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J. Biol. Chem., Vol. 278, Issue 33, 31372-31379, August 15, 2003
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From the Department of Biological Sciences, Columbia University, New York, New York 10027
Received for publication, April 22, 2003 , and in revised form, May 18, 2003.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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/
-fold that is conserved among members of the
DJ-1/ThiJ/PfpI superfamily. However, the structure also contains an extra
helix at the C terminus, which mediates a novel mode of dimerization for the
DJ-1 proteins. A putative active site has been identified near the dimer
interface, and the residues Cys-106, His-126, and Glu-18 may play important
roles in the catalysis by this protein. Studies with the disease-causing L166P
mutant suggest that the mutation has disrupted the C-terminal region and the
dimerization of the protein. The DJ-1 proteins may function only as dimers.
The Lys to Arg mutation at residue 130, the site of sumoylation of DJ-1, has
minimal impact on the structure of the protein. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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-synuclein (5), parkin
(6), and ubiquitin
carboxyl-terminal hydrolase L1
(7).
Most recently, it was discovered that mutations in the DJ-1 gene are linked with autosomal recessive early onset familial PD (8). Two types of disruptions of this gene have been identified in PD patients. One is a deletion of several of its exons, which abolishes the production of the DJ-1 protein. The other disruption is a single point mutation, giving rise to the L166P mutant at the protein level. This mutant has a different cytoplasmic distribution and is believed to be functionally inactive. Therefore, loss of the normal function of DJ-1 appears to contribute to PD.
The exact biological function of the DJ-1 protein is currently unknown. It
may play a role in the oxidative stress response, and this function could be
important in preventing the onset of PD
(8). Both -synuclein and
parkin participate in oxidative stress responses as well
(9,
10). On the other hand, DJ-1
may also be associated with several other biological processes. It was first
identified as an oncogene, because it can transform NIH3T3 cells in
cooperation with the ras oncogene
(11). The DJ-1 protein is also
involved in the fertilization process in rat and mouse
(12–14).
A significant reduction in the amount of this protein on the surface of sperm
makes them unable to fertilize eggs
(15). This finding suggests
that the protein may be secreted under some circumstances, which has also been
observed in breast cancers
(16). Finally, DJ-1 was
identified as the regulatory subunit of a 400-kDa RNA-binding protein complex
and its presence inhibits the binding of RNA by the complex
(17).
The DJ-1 protein is a positive regulator of the androgen receptor by
sequestering its negative regulators PIASx (protein inhibitor of
activated STAT) or DJBP (DJ-1-binding protein)
(18,
19). The activation of the
androgen receptor might be related to the effects of this protein on
fertility. PIAS proteins are SUMO-1 (small ubiquitin-like modifier-1) ligases
and control their target proteins by sumoylation
(20). It has been reported
that PIASx can sumoylate DJ-1 on the Lys-130 residue
(18). DJBP is almost
exclusively expressed in the testis in humans. It negatively modulates the
androgen receptor by recruiting histone deacetylases. DJ-1 can inhibit this
recruitment, thereby leading to the activation of the androgen receptor
(19).
The human DJ-1 protein contains 189 amino acid residues. It belongs to the DJ-1/ThiJ/PfpI superfamily of proteins, which are conserved in many different organisms (Fig. 1). The function of ThiJ is currently unknown, although it might be related to the biosynthesis of thiamin (21, 22). PfpI is an intracellular protease that was first identified from the archaeon Pyrococcus furiosus (23), and it is present in most bacteria and archaea. The crystal structure of the closely related intracellular protease PH1704 from Pyrococcus horikoshii revealed the presence of a Cys-100/His-101/Glu-74' catalytic triad (primed residue indicate a different monomer) with the active site at the interface of neighboring monomers in a hexameric oligomer (24). A Cys-185/His-186/Asp-214 catalytic triad was found in a structural homolog of this protease, the heat shock protein Hsp31 from E. coli (25). The amino acid sequence of this chaperone, however, shares only a 19% identity with that of PH1704. The DJ-1/ThiJ/PfpI proteins also share limited sequence and structural homology to those of the type I glutamine amidotransferase (GAT) domains, which contain a Cys-His-Glu/Asp catalytic triad (26).
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Although the Cys residue in the active site of the PfpI proteases is conserved among all of the members of the DJ-1/ThiJ/PfpI superfamily, the His and Asp/Glu residues are not conserved in DJ-1 and its close homologs (Fig. 1). To determine the composition of this putative active site in DJ-1 and to obtain a better understanding for the possible molecular function of this protein, we have determined its crystal structure at a 1.8-Å resolution. We have also characterized the disease-causing L166P mutant in solution, which suggests that the DJ-1 protein may function only as a dimer.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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For the production of selenomethionyl proteins, the expression construct was transformed into the methionine auxotroph E. coli DL41(DE3) cells. The bacterial growth was carried out in defined LeMaster media (27), and the protein was purified using the same protocol as for the wild-type protein.
Mutagenesis—The L166P and K130R single site mutants of human DJ-1 were created with the QuikChange kit (Stratagene) and sequenced to confirm the incorporation of the correct mutation. The mutant proteins were expressed in E. coli and purified following the same protocol as for the wild-type protein.
Protein Crystallization—Crystals of the DJ-1 wild-type and mutant proteins were prepared by the vapor diffusion method at 4 °C. Initial crystallization conditions for the wild-type protein were identified by sparse-matrix screening with commercial kits (Hampton Research). The reservoir solution contained 100 mM Tris (pH 8.0) and 10–12% (w/v) polyethylene glycol 3350. The protein was at a concentration of 15 mg/ml (diluted 1:1 with 30 mM Tris (pH 8.0) from the original stock). Both hexagonal bipyramid and plate crystals appeared overnight. They were cryoprotected with a solution containing 100 mM Tris (pH 8.0) and 35% (w/v) PEG3350 and flash-frozen in liquid propane. For crystals of the K130R mutant, the reservoir contained 100 mM Bis-Tris (pH 7.0), 20% (w/v) PEG3350, and 50 mM CaCl2. The protein was at 10 mg/ml concentration pre-mixed with 100 mM Bis-Tris (pH 5.5), 25% (w/v) PEG3350, and 200 mM ammonium acetate. Crystals in the shape of thin plates were cryoprotected with a solution containing 100 mM Bis-Tris (pH 7.0) and 35% (w/v) PEG3350 and flash-frozen in liquid propane for data collection at 100 K.
Data Collection and Processing—X-ray diffraction data were collected at 100 K on an ADSC (Area Detector Systems Corporation) CCD at the X4A beamline of Brookhaven National Laboratory. The diffraction images were processed and scaled with the HKL package (28). A selenomethionyl single wavelength anomalous diffraction data set to 1.8-Å resolution was collected on a hexagonal bipyramid crystal. It belongs to space group P3121, with one molecule in the asymmetric unit. The plate-shaped crystal of the wild-type protein belongs to space group P21 with four dimers in the asymmetric unit. A diffraction data set to 2.2-Å resolution was collected for this crystal. The K130R mutant crystal belongs to space group C2 with a dimer in the asymmetric unit. Its diffraction data set extended to 1.7-Å resolution. The data processing statistics are summarized in Table I.
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Structure Determination and Refinement—The locations of four Se atoms were determined with the program SnB (29). Reflection phases to 1.8-Å resolution were calculated based on the single wavelength anomalous diffraction data and improved with the program SOLVE (30), which also automatically located 80% of the residues in the molecule. The full atomic model was built into the electron density with the program O (31). The structures of the monoclinic crystal form and the K130R mutant were determined by the molecular replacement method with the program COMO (32). The structure refinement was carried out with the program CNS (33). The statistics on the structure refinement are summarized in Table I.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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We have also determined the crystal structure at 2.2-Å resolution of the wild-type protein in a monoclinic crystal form (Table I) by the molecular replacement method (32, 35). This crystal contains four dimers of DJ-1 in the asymmetric unit, allowing us to assess the conformational flexibility of the monomer and dimer of DJ-1.
The structure of the K130R mutant of human DJ-1 has been determined at 1.7-Å resolution by the molecular replacement method (Table I). This crystal form is not isomorphous to either of the native crystals. The structure shows that the K130R side chains in both monomers are involved in crystal-packing interactions with neighboring dimers in the crystal, and these interactions are different from those for the Lys-130 side chain in the wild-type crystals.
Structure of the DJ-1 Monomer—The structure of the monomer
of DJ-1 has the /-fold with 11 -strands
(1–11) and 8 -helices (A–H)
(Fig. 2A). The central
-sheet of the structure contains seven strands. The six parallel strands
of this sheet are arranged similar to those in the Rossmann-fold with the
distinction that the third strand is very short in the DJ-1 structure (5
with only two residues) (Figs.
1 and
2A). Outside the
central -sheet, strands 3 and 4 form a -hairpin
structure and are involved in the dimerization of DJ-1 (see below). Strands
8 and 9 together with helix F form a --
motif, which contributes the conserved His-126 residue to the putative active
site of DJ-1 (Fig.
2A).
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Most of the helices flank the two faces of the -sheet
(Fig. 2B). The only
exception is helix H at the extreme C terminus of DJ-1. It projects
away from the rest of the protein and only contacts helices A and
G in the monomer (Fig.
2B). Residues 181–187 in helix H are
conserved to be hydrophobic amino acids among the DJ-1 and ThiJ proteins
(Fig. 1). These residues
mediate the interactions with helices A and G as well as the
dimerization of DJ-1 (see below).
The Dimer of DJ-1—Gel-filtration and light-scattering
studies showed that wild-type DJ-1 protein exists as dimers in
solution.2 In the
trigonal crystal of the wild-type protein, there is a monomer of DJ-1 in the
asymmetric unit. The other monomer of the dimer is related by the
crystallographic 2-fold symmetry axis (Fig.
3A). The A helices of the two monomers come into
close contact in the core of the dimer
(Fig. 3B). At one edge
of the interface, the 3-4 hairpin is situated right next to the
dimer 2-fold axis, such that a four-stranded anti-parallel -sheet is
formed across the dimer (Fig.
3A). At the other edge, the 11-G loop
interacts with residues near the C terminus of the other monomer, including
those in helix H (Fig.
3B). These interactions may also be important to
stabilize the conformation of the H helix at the C terminus of
DJ-1.
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In the monoclinic crystal form of the wild-type protein, there are four
dimers in the asymmetric unit. Structural comparisons among these dimers and
the dimer in the trigonal crystal form show that the organizations of the
dimers are essentially the same. The r.m.s. distance between equivalent
C atoms of any pair of these dimers is approximately 0.35 Å. The
B helix shows conformational variability among the four dimers in the
monoclinic crystal, and this helix also has weak electron density in the
trigonal crystal. The organization of the dimer is also conserved in that of
the K130R mutant with a r.m.s. distance of 0.3 Å for 374 pairs of
equivalent C atoms of the wild-type and mutant dimers.
The DJ-1 dimer has an extensive interface between the two monomers. A total of 1200 Å2 of the surface area of each monomer is buried at this interface, involving mostly residues that are conserved among DJ-1 proteins (Fig. 1). Our structural and solution observations therefore suggest that this dimer is likely to be a stable and conserved oligomerization state for these proteins.
Interestingly, a deletion mutant of DJ-1 removing residues 178 to the C
terminus (Fig. 1) is still
mostly dimeric in solution (data not shown), suggesting that either the
H helix has a minor role in the dimerization of DJ-1 or the C-terminal
hexahistidine tag (LEHHHHHH) is partially rescuing the dimer formation. On the
other hand, the deletion mutant lacking residues 173 to the C terminus forms
large aggregates of various sizes (molecular masses of 200–400 kDa) with
little dimeric species in solution.
Structural Homologs of DJ-1—The structure of DJ-1 bears the
strongest similarity to that of PH1704 from P. horikoshii
(24), a member of the PfpI
family, and the two proteins share 22% amino acid sequence identity. The
r.m.s. distance is 1.1 Å for 137 equivalent C atoms between DJ-1
and PH1704. Most of the secondary structure elements are superimposable
between the two proteins (Fig.
2C). However, the H helix at the C terminus of
DJ-1 does not have a structural equivalent in PH1704. Sequence comparisons
suggest that all of the PfpI family members lack this helix, because they are
approximately 15 residues shorter than DJ-1 at the C terminus
(Fig. 1).
The quaternary structure of PH1704 and DJ-1 are entirely different, despite
the homology in the sequence and structure of their monomers. In contrast to
the dimeric association of DJ-1, a hexameric structure roughly obeying 32
symmetry was observed in the crystal of PH1704
(24). This hexamer can be
considered as a trimer of dimers, and the interface of the dimer is mediated
by the A and G helices. However, such a mode of dimerization is
not possible with DJ-1 as it is blocked by the extra H helix in DJ-1.
Therefore, the DJ-1 dimer is formed by a different arrangement of the A
and G helices of the two monomers and the H helices also
contribute to the dimerization interface
(Fig. 3A). In
addition, the contribution of the 3–4 hairpin to the dimer
interface is unique to DJ-1 (Fig.
3A). The dimerization of Hsp31, a structural homolog of
PH1704 and DJ-1, is mediated by segments outside the PfpI/DJ-1-fold
(25).
Searches against the Protein Data Bank with the program Dali
(36) showed that DJ-1 also
shares significant structural similarity with the C-terminal domain in the
catalase hydroperoxidase II (HPII)
(37) as has been suggested
earlier (26). The r.m.s.
distance for 136 equivalent C atoms between DJ-1 and this C-terminal
domain (residues 600–753) is 2.0 Å. The amino acid identity for
these residues is however only 12%. This domain in HPII lacks the
8–10 insertion (Fig.
2D), which accounts for its smaller size. At the C
terminus, HPII also has a helix but it is running in an opposite direction
from the H helix in DJ-1. The exact function of this C-terminal domain
in HPII is not fully understood. It mediates the dimer interface in the
tetramer of the enzyme and helps to form the substrate channel leading to the
active site (37). This domain
may also facilitate the folding of the full-length enzyme, as deletion mutants
lacking this domain cannot accumulate in the cell. The dimerization of this
domain in HPII uses the unique H helix at the C terminus and is
different from that in DJ-1.
Structural homology between the DJ-1/ThiJ/PfpI superfamily and the GAT
domains has also been suggested earlier
(26). However, the actual
similarity is rather limited. The GAT domains lack the 3–4
hairpin structure in DJ-1 but contain significantly more elaborate insertions
between E and 10. Moreover, the binding site for glutamine in GAT
is blocked by the 6-C loop in the DJ-1 structure. Therefore, it
is unlikely that DJ-1 can have GAT function.
The Putative Catalytic Residues of DJ-1—The exact
biochemical function of the DJ-1 protein is currently not known. However,
structural and sequence comparisons with homologous proteins can provide
valuable hints as to the possible roles of this protein in oxidative stress
response, androgen receptor regulation, and other processes. A cysteine
residue is conserved among all of the members of the DJ-1/ThiJ/PfpI
superfamily, and the residue has been proposed as the catalytic nucleophile
for the PfpI family of intracellular proteases
(24). This residue is
equivalent to Cys-106 in human DJ-1 (Fig.
1) and is located just after strand 7 in the structure
(Fig. 2A). The main
chain of this residue assumes a strained conformation with 
and 
torsion angles of 66 and –114°, respectively, which is also observed
in the structures of PH1704 and Hsp31
(24,
25). The structural
conservation of this Cys residue in DJ-1 suggests that it may also have a
catalytic role in the biochemical function of this protein, identifying this
region of the structure as the putative active site of DJ-1.
In both the PfpI proteases and the Hsp31 chaperone, the Cys residue is part
of a Cys-His-Asp/Glu catalytic triad
(24,
25). The second member His
residue in the triad follows immediately after the Cys residue in the primary
sequence of these proteins (Figs.
1 and
2C). In DJ-1, however,
the residue immediately after Cys-106 is Ala
(Fig. 1), signifying that there
are differences between DJ-1 and the PfpI proteases in this active site. Our
structures show that His-126, from the 8-F loop and conserved
among all of the DJ-1 proteins (Fig.
1), is placed near the Cys-106 side chain in the putative active
site of DJ-1 (Fig.
4A). The His-126 residue could be the second member of
the catalytic machinery for DJ-1. The distance between the side chains of
Cys-106 and His-126 is 4.2 Å in the current structure
(Fig. 4A) similar to
the distance of approximately 5 Å that is found in the active site of
caspases (38).
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Simultaneous mutation of three residues of DJ-1, S57R, E96G, and H126Y can
disrupt the interactions with PIASx
(18), providing support for
the functional importance of the His-126 residue. However, all of the three
residues are strictly conserved among the DJ-1 proteins
(Fig. 1) and both Ser-57 and
Glu-96 appear to have important structural roles as well. Therefore, it is not
clear which of the three mutations is responsible for the loss of activity.
The three residues are separated by 
25 Å from each other in the
structure, so it is unlikely that they can all mediate the interactions with
PI-ASx at the same time.
In PH1704, the third member Glu residue of the catalytic triad comes from another monomer in the enzyme oligomer (Fig. 2C) (24), whereas in Hsp-31, the third member Asp residue comes from an inserted segment to the DJ-1/ThiJ/PfpI-fold (25). In our structures of DJ-1, no acidic residues are positioned near the His-126 side chain. The active site of the DJ-1 family members may contain only a Cys-His diad. With a cysteine residue as the nucleophile, it is known that a Cys-His diad is fully functional, for example, in the caspases.
On the other side of the Cys-106 residue, the side chain of Glu-18 is
within 3.2 Å of the S
atom in the structure of DJ-1
(Fig. 4A). This Glu
residue is strictly conserved among all of the DJ-1/ThiJ/PfpI proteins
(Fig. 1), and it is also
present in Hsp31. Moreover, the side chain of this residue is completely
buried in the structure. Therefore, it is likely that this residue also has an
important role in the biochemical functions of these proteins.
The Putative Active Site of DJ-1—The putative active site of
DJ-1 is located near the interface of the dimer with contributions from
residues in helices A and H of the other monomer
(Fig. 4A). The two
monomers of the dimer are arranged in a head-to-tail fashion, such that the
two active sites are on opposite sides of the dimer
(Fig. 3A). The Cys-106
residue lies in the center of a prominent surface depression in the structure
(Fig. 4B). Residues in
this active site are generally highly conserved including the
74GGNLGA79 motif (6-C loop) and the
157GPG159 motif (8-F loop)
(Fig. 4A) that are
conserved among the DJ-1 and ThiJ proteins
(Fig. 1). The A helix
plays an especially important role in this active site. The Glu-18 residue is
located near the N terminus of this helix, whereas Asp-24 and Arg-28 near its
C terminus contribute to the other active site of the dimer
(Fig. 4A).
Near Cys-106, there is a cluster of three acidic residues (Glu-15, Glu-16,
and Asp-24') and two basic residues (Arg-48 and Arg-28')
(Fig. 4A). These
residues are highly conserved among all of the members of the DJ-1/ThiJ/PfpI
superfamily (Fig. 1). The side
chain of Glu-16 may stabilize the conformation of the 3-4 hairpin
by hydrogen bonding to residues 47 and 48 at its tip
(Fig. 4A). Glu-15 is
the N-terminal cap of helix A and is hydrogen-bonded to the main chain
amide of residue 17. In addition, this residue interacts with Asp-24'
and Arg-28', helping the formation of the dimer. It is likely that
Arg-48 and Arg-28' are involved in the binding of the substrate of this
protein (Fig. 4A).
The Structure of the K130R Mutant, Site of Sumoylation—It
has been reported that the Lys-130 residue can become sumoylated and that this
modification is important for DJ-1 to achieve full activity in cell
transformation (18). In the
crystal structure, the Lys-130 residue is located at the beginning of helix
F, 10 Å from the His-126 residue, and its side chain is
completely exposed to the solvent (Fig.
5). Our structure of the K130R mutant of DJ-1 showed that the
mutation has little impact on the structure of the protein itself. The Arg-130
side chains in the two monomers assume different conformations
(Fig. 5), but this is probably
due to the fact that the two Arg residues are involved in different
crystal-packing contacts. The structural observation is consistent with the
fact that the K130R mutation does not disrupt the interaction with the
PIASx protein (18).
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Studies on the Disease-causing L166P Mutant—The L166P mutation of human DJ-1 was first found in an Italian PD patient (8). This residue is strictly conserved among the DJ-1 proteins (8) as well as the ThiJ proteins, although it is not conserved among the PfpI proteases (Fig. 1). Based on sequence homology between DJ-1 and the PH1704 protease, it was suggested that the Leu-166 residue is located in a helix and the L166P mutation may disrupt the formation of this helix (8).
Our structural analyses confirm that Leu-166 is located in the center of
helix G (Fig.
2B). Moreover, our structures show that the side chain of
this residue has a major role in forming the hydrophobic core between the
extra H helix at the C terminus and the A and G helices
(Fig. 6). A total of 78
Å2 of the surface area of Leu-166 is buried at this
interface. Therefore, the L166P mutation may have two effects on the structure
of DJ-1 destabilization/unfolding of the G helix and the disruption of
the hydrophobic core among helices A, G, and H.
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To further characterize the structure of the L166P mutant, we have expressed it in E. coli and purified the soluble protein by nickel affinity, anion exchange, and gel filtration chromatography. Efforts at producing crystals of this mutant have so far been unsuccessful. Light-scattering studies with the purified protein show that the mutant is monomeric in solution. This is consistent with the structural analysis that the L166P mutation may lead to the unfolding of the C-terminal segment of DJ-1, which will also disrupt the formation of the dimer. These results suggest that the DJ-1 protein may only function as a dimer.
Functional Implications—Based on overall sequence homology,
the DJ-1, ThiJ, and PfpI proteins have been grouped together into a
superfamily. With the structural information on DJ-1 and PfpI (PH1704), it is
clear that there are significant structural and sequence differences among the
members of the superfamily. DJ-1 and ThiJ proteins may be more closely related
to each other, whereas the PfpI proteins are more distant. Examination of the
amino acid sequence conservation suggests that ThiJ proteins might also have
the H helix at the C terminus (Fig.
1) similar to DJ-1, whereas the PfpI proteins do not. The
conservation of the Leu-166 residue in the DJ-1 and ThiJ proteins is probably
related to the presence of this extra helix, because it is a crucial component
of the hydrophobic core between this helix and the rest of the protein
(Fig. 6). It is also possible
that the ThiJ proteins will form the same dimer as DJ-1, in contrast to
PH1704. The disease-causing effects of the L166P mutation in DJ-1 underscores
the functional importance of the structural integrity of the C-terminal
segment and indicates that these proteins may function only as dimers.
Another difference among members of this superfamily is that the active site His residue immediately follows the catalytic Cys nucleophile in the primary sequence only in the PfpI proteins. Although DJ-1 and ThiJ are similar in maintaining an Ala residue at this position in the primary sequence, the His-126 residue identified from our structural studies is conserved only in DJ-1. Based on the structural information and the sequence alignment, it is unlikely that the ThiJ proteins contain a His residue in the active site. However, the Glu-18 residue is still conserved in ThiJ.
DJ-1 has been associated with many different biochemical and biological functions. Our structural analysis suggests that DJ-1 may possess an active site and could also be a protease/hydrolase similar to the PfpI proteases. The relative positioning of the Cys-106 and His-126 residues are reminiscent of the active site of caspases. In addition, Arg-48 and Arg-28' residues are approximately 8 Å away from the Cys-106 residue in DJ-1, similar to the distances for the two Arg residues that recognize the P1 Asp residue in the substrate of caspases. It would be interesting to determine whether DJ-1 can recognize Asp residues in this putative active site.
The DJ-1 protein can also mediate interactions with other proteins such as
PIASx, DJBP, and the RNA-binding protein complex. It is not known
whether the putative catalytic activity of DJ-1 is required for these
interactions or whether a different surface patch can mediate these
interactions. The structural conservation between DJ-1 and a domain that is
crucial for the function of HPII and other catalases offers the tantalizing
possibility that DJ-1 may also regulate the dismutation of peroxides. This
could be the link between DJ-1 and the oxidative stress response.
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FOOTNOTES |
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* This work was supported by National Institutes of Health Grant AI49475 (to
L. T.). 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. Tel.: 212-854-5203; Fax:
212-854-5207; E-mail:
tong{at}como.bio.columbia.edu.
1 The abbreviations used are: PD, Parkinson's disease; PIASx, protein
inhibitor of activated STAT; STAT, signal transducers and activators of
transcription; DJBP, DJ-1-binding protein; GAT, glutamine amidotransferase;
r.m.s., root mean square; HPII, hydroperoxidase II.
2 X. Tao and L. Tong, unpublished data.
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ACKNOWLEDGMENTS |
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REFERENCES |
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