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(Received for publication, March 15, 1996, and in revised form, June 6, 1996)
From the Department of Biological Sciences, Columbia University,
New York, New York 10027
ABSTRACT C129/U1 is a respiratory defective mutant of
Saccharomyces cerevisiae arrested in cytochrome oxidase
assembly due to a mutation in COX17, a nuclear gene
encoding a low molecular weight cytoplasmic protein proposed to
function in mitochondrial copper recruitment. In the present study we
show that the respiratory defect of C129/U1 is rescuable by two
multicopy suppressors, SCO1 and SCO2. SCO1 was
earlier reported to code for a mitochondrial inner membrane protein
with an essential function in cytochrome oxidase assembly (Buchwald,
P., Krummeck, G., and Rodel, G. (1991) Mol. Gen. Genet.
229, 413-420). SCO2 is a homologue of SCO1,
whose product is also localized in the mitochondrial membrane but is
not required for respiration.
SCO1 also suppresses a cox17 null mutant,
indicating that overexpression of Sco1p can compensate for the absence
of Cox17p. In contrast, neither copper, COX17 on a
multicopy plasmid, or a combination of the two is able to restore
respiration in sco1 mutants. Rescue of cox17
mutants by Sco1p suggests that this mitochondrial protein plays a role
either in mitochondrial copper transport or insertion of copper into
the active site of cytochrome oxidase. Although SCO2 can
also partially restore respiratory growth in the cox17 null
mutant, rescue in this case requires addition of copper to the growth
medium. SCO2 does not suppress a sco1 null
mutant, although it is able to partially rescue a sco1
point mutant. We interpret the ability of SCO2 to restore
respiration in cox17, but not in sco1 mutants,
to indicate that Sco1p and Sco2p have overlapping but not identical
functions.
INTRODUCTION The COX17 gene of Saccharomyces cerevisiae
has been shown to code for a cytoplasmic protein that is essential for
assembly of cytochrome oxidase (1). The respiratory defect of
cox17 mutants is correctable by exogenous copper, indicating
an insufficiency of mitochondrial copper as the basis for the assembly
arrest. Cox17p is a low molecular mass protein (8 kDa) with 7 cysteine
residues, of which at least one is functionally important (1). The
copper deficiency in cox17 mutants appears to be confined to
cytochrome oxidase. The presence in a cox17 null mutant of
cytoplasmic superoxide dismutase (2) and the iron transporter encoded
by FET3 (3), both of which use copper as cofactors, provides
strong evidence that Cox17p targets copper to mitochondria (1).
The COX17 gene was cloned by complementation of the
cytochrome oxidase deficiency of the cox17 mutant, C129/U1,
with a yeast genomic plasmid library (1). Transformations of this
mutant yielded two other plasmids that did not contain
COX17. In this communication, we show that these high copy
suppressors of C129/U1 are SCO1 (4) and SCO2 (5).
SCO1 has been reported to code for a cytochrome oxidase
assembly factor (4). SCO2 was identified through the yeast
genome sequencing project (5). Although the two genes code for
homologous proteins, a null mutation in SCO2 does not elicit
a discernable phenotype. Sco1p and Sco2p are both membrane constituents
of mitochondria, but do not appear to be associated in a stable
complex. Suppression of cox17 mutants by SCO1
indicates that the product of this gene also plays a role in providing
copper for cytochrome oxidase. The failure of sco1 mutants
to form the mature complex is proposed to be caused either by a
deficiency in mitochondrial copper uptake or by failure to insert
copper during assembly of cytochrome oxidase.
MATERIALS AND METHODS The genotypes and sources of the
strains of S. cerevisiae used in this study are listed in
Table I. The media used for growth of yeast have been
described elsewhere (1).
Genotypes and sources of yeast strains
Volume 271, Number 34,
Issue of August 23, 1996
pp. 20531-20535
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Strain
Genotype
Source
W303-1A
a
ade2-1 his3-1,15 leu2-3,112 trp1-1
ura3-1
a
W303-1B
ade2-1
his3-1,15 leu2-3,112 trp1-1 ura3-1
a
C129/U1
ura3-1 cox17-1Ref. 1
E428
met6 sco1Ref. 6
E428/U1
ura3-1 sco1E428 × W303-1A
W30
a
ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 sco1
This
study
W303
COX17
ade2-1 his3-1,15 leu2-3,112
trp1-1 ura3-1 cox17::TRP1Ref. 1
W303
SCO2
ade2-1 his3-1,15 leu2-3,112 trp1-1
ura3-1 sco2::URA3This study
aW303
SCO1a ade2-1 his3-1,15 leu2-3,112
trp1-1 ura3-1
sco1::URA3This study
aW303
SCO1/ST12a ade2-1 his3-1, 15 leu2-3,112 trp1-1 ura3-1
sco1::URA3
leu2::SCO1-BIOThis study
a
Dr. Rodney Rothstein, Department of Human Genetics,
Columbia University.
ABSTRACTThe SCO1 and SCO2 genes were cloned by transformation of the cox17 mutant, C129/U1, with a recombinant library of yeast nuclear DNA, by the method of Schiestl and Gietz (7). The library used for the transformation was constructed from partial Sau3A fragments of nuclear DNA (averaging 7-10 kb)1 cloned into the BamHI site of the shuttle vector YEp24 (8). This library was kindly provided by Dr. Marian Carlson, Department of Genetics and Development, Columbia University. Approximately 5 × 108 cells were transformed with 100 µg of plasmid DNA. The transformation mixtures were plated on minimal glucose medium to select for plasmid-bearing clones (approximately 105 uracil-positive clones). The minimal glucose plates were replicated on rich glycerol medium, and growth was scored after 2-5 days of incubation at 30 °C. SCO1 was also cloned independently by transformation of the sco1 mutant E428/U1 with the same genomic library.
Preparation of Yeast Mitochondria and Enzyme AssaysWild-type and mutant yeast were grown to stationary phase in YPGal (2% galactose, 1% yeast extract, and 2% peptone) and mitochondria were prepared by the procedure of Faye et al. (9), except that Glusulase was replaced by Zymolyase 20,000 (ICN Biomedicals, Inc.) to prepare spheroplasts. Cytochrome oxidase activity was measured by following oxidation of ferrocytochrome c at 550 nm (10).
Construction of a SCO1-BIO Fusion GeneTo create a gene expressing Sco1p with covalently attached biotin at its carboxyl terminus (11), the termination codon of SCO1 was destroyed and replaced by a BamHI site. A HindIII site was created 296 bp upstream of the start codon, and the amplified 1.2-kb fragment was digested with HindIII and BamHI and cloned into YEp352-Bio5. The resultant construct consisted of the entire SCO1 coding sequence fused in-frame to the 270-nucleotide fragment coding for the biotinylation signal sequence of bacterial transcarboxylase (12). The fusion gene was transferred to the multicopy shuttle vector YEp351 and to the integrative plasmid YIp351 (13).
Construction of W303SCO1 and W303SCO2
A null allele
of SCO1 was made by cloning the 1.7-kb EcoRI
fragment containing SCO1 into YEp352E. YEp352E is identical
to YEp352 (13), except that the multiple cloning region of the latter
plasmid is replaced with a unique EcoRI site. This plasmid
was linearized at the SphI site inside SCOI
and ligated to a 1.2-kb linear SphI fragment with the
yeast URA3 gene. Respiratory deficient and
uracil-independent transformants (W303SCO1) were obtained and
verified to have the disrupted allele by backcrosses to a
sco1 mutant and by Southern analysis of genomic DNA.
The sco2::URA3 allele was created by replacement
of the 450-bp AflII fragment internal to the coding sequence
with the URA3 gene. pSG74/ST4 was digested with
AflII, and the linear plasmid was ligated to an
SphI linker. The yeast URA3 gene (as a 1.1-kb
SphI fragment) was ligated to the SphI site in
the gapped gene. The disrupted sco2::URA3 allele
was isolated on a linear fragment and used to transform the respiratory
competent haploid strains W303-1A and W303-1B by the one-step gene
replacement procedure (14). Uracil-independent transformants were
selected and verified to have the disrupted alleles by Southern
analysis of their chromosomal DNA (see Fig. 2).
Fig. 2. Southern analysis of W303
SCO2 genomic
DNA. The construction of the sco2::ura3 null
allele is shown in the lower part of the figure. The 450-bp
AflII fragment was removed from pSG74/ST4 (see Fig. 1) and
replaced by an SphI linker. After transfer of the insert to
pUC8, the construct was linearized with SphI and ligated to
the URA3 gene. The delineating SmaI
(Sm) and PstI (P) sites of pSG74/ST4,
as well as the two AflII (A) sites are indicated
on the map. aW303SCO2 is a uracil prototroph obtained by
transformation of W303-1A with the linear fragment containing the
disrupted gene. Chromosomal DNA from both the SCO2 disrupted
and wild-type strains was digested with PstI and
SmaI, separated on a 1% agarose gel, and transferred to
nitrocellulose. The blot was hybridized with the entire pSG74/ST4
insert. The probe detects the homologous 1.9-kb band in W303-1A and a
1.1-kb band in the mutant (SCO2). The novel 1.1-kb band
consists of the upstream and coding region of SCO2 and 200 bp of the URA3 fragment up to the PstI site. Not
seen on the photograph is a second hybridizing band of approximately
0.6 kb representing the 3
-untranslated region of SCO2 and
60 bp of the URA3 disruptor. The migration of DNA size
standards is shown in the left hand margin.
Preparation of Antibodies to Sco2p
In order to generate
antibodies to the SCO2 gene product, the gene was amplified
by PCR, with primers which created a BamHI site at amino
acid residue 11 and a HindIII site 120-bp downstream of the
stop codon. This fragment was ligated into the expression vector pATH20
(15), creating an in-frame fusion with the Escherichia coli
trpE gene. The fusion protein expressed from the trpE
fusion constituted most of the insoluble protein fraction of the
E. coli cells. This fraction was dissolved in a 10 mM Tris-HCl, 1 mM EDTA, pH 7.5 buffer,
containing 2% SDS, 5 mM 
-mercaptoethanol, and 20 µg/ml phenylmethylsulfonyl fluoride, and the Sco2-fusion protein was
further purified on a Bio-Gel A0.5 column developed with a buffer
containing 10 mM Tris-HCl, 0.1 mM EDTA, and 5 mM -mercaptoethanol. Fractions containing primarily the
fusion protein were pooled, concentrated by acetone precipitation, and
used to raise antibodies in rabbits.
Standard procedures were used for the preparation and ligation of DNA fragments and for transformation and recovery of plasmid DNA from E. coli (16). The preparation of yeast nuclear DNA and the conditions for the Southern hybridizations were as described by Myers et al. (17). DNA probes were labeled by random priming (18), and DNA was sequenced by the method of Maxam and Gilbert (19). Proteins were separated by polyacrylamide gel electrophoresis in the buffer system of Laemmli (20), and Western blots were treated with antibodies against Sco2p followed by a second reaction with 125I-protein A (21). Alternatively, biotin-containing proteins were visualized with peroxidase conjugated to avidin (1). Protein concentrations were determined by the method of Lowry et al. (22).
RESULTS
C129 is a
cytochrome oxidase defective mutant of S. cerevisiae with a
single point mutation in COX17 (1). The COX17
gene was cloned by complementation of C129/U1 with a yeast genomic
library (1). Some of the respiratory competent clones obtained from the
transformations, however, were found to have plasmids with genomic
fragments unrelated to one another or to COX17. The physical
maps of two such plasmids indicated the presence of SCO1, a
gene coding for a cytochrome oxidase assembly factor (4, 23). The
identity of SCO1 as the suppressor was corroborated by the
ability of pG41/T2 and pG41/ST8 to confer respiration to C129/U1.
pG41/T2 was cloned independently by transformation of a sco1
mutant. pG41/ST8 is a subclone of pG41/T2 containing only
SCO1 (Fig. 1).
Fig. 1. Restriction maps of pG41/T2, pSG74/T1, and subclones. The locations of the XbaI (X), EcoRI (E), SphI (Sp), BglII (G), SmaI (Sm), AflII (A), and PstI (P) sites are marked in the nuclear inserts of pG41/T2 and pSG74/T1, drawn as single lines. The YEp24 vector is denoted by the hatched bars with the unique SphI site shown to provide an orientation of the inserts. The location and direction of transcription of the SCO1 (pG41/T2) and SCO2 (pSG74/T1) genes are indicated by the solid black arrows. The horizontal lines above the nuclear inserts show the subclones used to transform C129/U1.
SCO1 codes for a constituent of the yeast mitochondrial inner membrane and is essential for the expression of cytochrome oxidase (4, 23). Mutations in SCO1 induce a specific deficiency in cytochrome oxidase but do not substantially affect other enzymes of the respiratory chain or of the ATPase (4, 23). The ability of sco1 mutants to synthesize the mitochondrial encoded subunits of cytochrome oxidase (23) and to accumulate the nuclear gene products has led to the suggestion that Sco1p promotes some late post-translational step in the assembly pathway (4, 23), although its precise function has not been clarified.
Two other plasmids (pSG74/T1 and T2) obtained by transformation of C129/U1 had overlapping inserts unrelated to either COX17 or SCO1 (Fig. 1). Partial sequencing of the insert in pSG74/T1 revealed that it contained a fragment of yeast chromosome II with SCO2, a homologue of SCO1 (5). Restoration of respiration in C129/U1 by pSG74/ST4, but not by pSG74/ST5 (with a 450-bp deletion in the SCO2-coding region), confirmed SCO2 to be a second high copy suppressor. The function of the SCO2 product is not known. The phenotype of a mutant with a null allele of the gene (see below) precludes a requirement for the protein in respiration.
Phenotype of a sco2 Mutant and Localization of the ProductTo
facilitate further studies on the relationship of Cox17p to Sco1p and
Sco2p, null alleles of SCO1 or SCO2 were
constructed as described under ``Materials and Methods.'' Mutants
with a disrupted chromosomal copy of SCO1 (aW303SCO1) are
unable to grow on nonfermentable carbon sources and exhibit a
deficiency in cytochrome oxidase, as reported previously (4). In
contrast, W303SCO2, carrying a null mutation in SCO2, had
a respiratory competent phenotype and normal levels of cytochrome
oxidase. The replacement of the wild-type gene by the
sco2::URA3 allele in W303SCO2 was confirmed by
a genomic Southern (Fig. 2). Additional evidence for the
absence of Sco2p in W303SCO2 was obtained by immunological assays of
Sco2p in mitochondria from the mutant, the parental wild-type strain,
and a transformant harboring SCO2 on a multicopy plasmid.
Western analysis of total mitochondrial proteins, with an antibody
against the protein expressed from the SCO2/trpE fusion
gene, indicates the presence of a protein of approximately 30 kDa in
wild-type mitochondria (Fig. 3A). This mass
is consistent with the molecular mass of Sco2p based on the derived
protein sequence, assuming that some 4 kDa are lost during processing
of the precursor. The 30-kDa protein detected by the antibody is much
more abundant in mitochondria from a transformant harboring
SCO2 on a high copy plasmid and is absent in W303SCO2.
The absence of a signal in the null mutant confirms that this
mitochondrial constituent is not required for respiration. Mitochondria
from two other strains were also probed with the same antibody.
W303SCO1 has a disrupted chromosomal copy of SCO1, and
W303SCO1/ST12 is the identical mutant transformed with a fusion gene
expressing biotinylated Sco1p-Bio, approximately 7 kDa larger than the
native protein. The absence of a cross-reacting protein of 37 kDa in
mitochondria from W303SCO1/ST12 and the lack of an effect of the
sco1 mutation on the strength of the signal indicates that
the antibody specifically recognizes Sco2p.
Fig. 3. Localization of Sco2p in yeast mitochondria. Panel A, mitochondria were prepared from the wild-type strain W303-1B (WT), the SCO2-disrupted strain (
SCO2), C129/U1 transformed with SCO2
on a multicopy plasmid (ST4), W303SCO1 with a disrupted
copy of SCO1 (SCO1), and W303SCO1/ST12
expressing a biotinylated Sco1p fusion protein
(SCO1/ST12). Approximately 30 µg of total mitochondrial
protein were separated on a 12% polyacrylamide gel, transferred to
nitrocellulose, and probed with an antibody against the
SCO2-TrpE fusion protein. The cross-reacting bands were
visualized with 125I-protein A. The migration of molecular
mass standards is indicated in the left-hand margin. Panel
B, mitochondria from the wild-type strain (W303-1B) were suspended
at a concentration of 10 mg/ml and disrupted by sonication. The
membrane and soluble protein fractions were separated by centrifugation
at 105,000 × g for 30 min. The submitochondrial
particles were resuspended in buffer and adjusted to the starting
volume of mitochondria. The mitochondria (M),
submitochondrial particles (P), and supernatant
(S) fractions were separated on a polyacrylamide gel and
probed with the antibody to Sco2p as described above. Panel
C, submitochondrial particles of wild-type yeast were extracted in
the presence (lanes 2-6) or absence (lane 1) of
0.5 M NaCl and increasing concentrations of deoxycholate,
as follows: lane 1, 0%; lane 2, 0%; lane
3, 0.1%; lane 4, 0.2%; lane 5, 0.5%; and
lane 6, 1.0%. The pellets were resuspended to the starting
volume and pellet (P) and supernatant (S)
fractions run on a 12% polyacrylamide gel as described in panel
A.
The Sco2p antibody was used to determine whether this protein is a mitochondrial membrane protein like Sco1p. Mitochondria prepared from the respiratory competent strain W303-1B were disrupted by sonication and the membrane and soluble fractions were probed for Sco2p. The Western blot, shown in Fig. 3B, indicates Sco2p to be present exclusively in the submitochondrial membrane fraction. Solubilization of Sco2p requires extraction of mitochondria with 0.2-0.5% deoxycholate and 0.5 M NaCl, further confirming the hydrophobic nature of this protein (Fig. 3C).
Suppression of a cox17 Null Mutant by SCO1 and SCO2C129/U1
has a point mutation in COX17 resulting in the substitution
of a tyrosine for the carboxyl-proximal cysteine in the protein (1). To
test if overexpression of SCO1 and SCO2 can also
suppress a cox17 null mutant, W303COX17, harboring a
disrupted copy of COX17, was transformed with pG41/ST8
(SCO1), pSG74/ST4 (SCO2), and as a control, also
with pG74/ST8, a multicopy plasmid containing COX17. The
respiratory competent parental strain, W303-1B, and the different
transformants were replicated on rich glycerol/ethanol medium (YEPG)
and scored for growth after 3 days of incubation at 30 °C (Fig.
4, top plate). The null mutant was partially
suppressed by SCO1, but not by SCO2 (Fig. 4,
top plate). The generation time of the mutant transformed
with SCO1 was approximately double that of the wild-type
strain.
Fig. 4. Suppression of a cox17 null mutant by overexpression of SCO1 and SCO2. The respiratory competent strain W303-1B (W303), the cox17 null mutant W303
COX17 (COX17), and
W303COX17 transformed with CTR1
(COX17/CTR1), COX17
(COX17/COX17), SCO2
(COX17/SCO2), and SCO1
(COX17/SCO1) were streaked on rich glucose medium and
replica-plated onto rich ethanol/glycerol (top plate), and
rich ethanol/glycerol supplemented with either 0.1% CuSO4
(middle plate) or 0.4% CuSO4 (bottom
plate). The replica plates were incubated for 3-4 days at
30 °C.
Growth of C129/U1 and W303COX17 on mitochondrial substrates is
rescued by addition of exogenous copper to the growth medium (1). The
effect of copper supplementation was also tested on the
cox17 mutants transformed with SCO1 and
SCO2. The somewhat leaky growth phenotype of C129/U1 made it
difficult to score differences in the growth of this strain as a
function of the different plasmids and the copper supplement. In the
case of W303COX17, copper supplementation clearly enhanced the
suppressor activity of SCO1 with the null mutant. Addition
of copper to the medium also allowed SCO2 to partially
suppress the respiratory defect in the null mutant (Fig. 4,
middle plate), at a concentration lower than that required
to rescue the null mutant itself (Fig. 4, bottom plate).
Suppression by SCO1, and to a lesser degree by SCO2, of the cytochrome oxidase deficiency of cox17 mutations suggested that the products of the two genes might be involved in mitochondrial copper metabolism. Unlike cox17 mutants, neither the sco1 null mutant, nor seven independent sco1 point mutants were rescued by inclusion of 0.01-0.8% copper in the medium. Neither were the mutants rescued with high copy numbers of either COX17 or CTR1 (the structural gene for the plasma membrane copper pump) (25), either in the presence or absence of added copper. In previous studies, the concentration of copper needed to restore respiratory growth of the cox17 null mutant could be significantly lowered (>10-fold) when it was transformed with CTR1 on a high copy plasmid (1). Overexpression of the plasma membrane copper pump was presumed to increase internal copper pools, thereby allowing rescue to occur in the presence of lower exogenous copper (1).
Allele-specific Suppression of a sco1 Mutation by SCO2The
primary sequence homology of Sco1p and Sco2p, and their activity as
suppressors of the cox17 allele in C129/U1, suggested that
they might have similar or overlapping functions. Transformation of
W303SCO1 with SCO2 (pSG74/ST4), however, failed to
restore respiratory growth in the sco1 null mutant,
indicating that the two proteins are not exchangeable and therefore
cannot be functionally equivalent. When tested for suppression of point
mutations, SCO2 was found to partially rescue one of the
seven sco1 mutants tested (W30).
The allele-specific suppression of a sco1 mutant by SCO2 could indicate that a physical interaction of Sco1p and Sco2p is necessary for function. This is contradicted by the observation that the sco2 null mutant has no phenotype on nonfermentable carbon sources. Attempts to detect a physical complex of the two proteins also were unsuccessful. Extraction of Sco1p-Bio and purification of the biotinylated protein by affinity chromatography on a monomeric avidin column failed to disclose copurification of Sco2p. Secondly, although both Sco1p and Sco2p sediment with apparent molecular masses of approximately 60 kDa, the sedimentation behavior of Sco2p was the same in a strain with a sco1 null mutation (data not shown). Finally, suppression by overexpression of Sco1p or Sco2p alone is difficult to rationalize if the two proteins are subunits of a stoichiometric complex.
DISCUSSION
The cytochrome oxidase deficiency of cox17 mutants was
previously shown to be corrected by exogenous copper (1). This
observation together with the cytoplasmic localization of Cox17p led us
to propose a role for this low molecular weight protein in targeting
copper to mitochondria (1). In the present study we demonstrate rescue
of cox17 mutants, including a strain with a null allele of
the gene, by overexpression of Sco1p, a constituent of the
mitochondrial inner membrane, encoded by SCO1 (23). The
suppressor activity of SCO1 suggests an involvement of the
product, Sco1p, in mitochondrial copper metabolism. Since
sco1 mutants are not rescued by COX17, Sco1p is
likely to act downstream of Cox17p, either prior to or during the
copper maturation step. An alignment of yeast Sco1p with several
homologues from eucaryotic and procaryotic sources reveals a potential
copper binding domain characterized by the presence of two conserved
cysteines whose spacing and proximity to a short conserved hydrophobic
domain is reminiscent of the copper binding domain of subunit 2 of
cytochrome oxidase (Fig. 5).
Fig. 5. Alignment of yeast Sco1p and Sco2p with other Sco-like proteins and with the copper binding domain of cytochrome oxidase subunit 2. The copper binding domain of subunit 2 (Cox2p) of yeast cytochrome oxidase (26) is aligned with a domain containing two conserved cysteine residues present in all known members of the SCO family. The amino acid residues are numbered in the left-hand margin and the sources of the proteins are indicated in the right-hand margin. The references for the different sequences are: Yeast Sco1p (4), Yeast Sco2p (5), Rhodobacter (capsulatus) (27), Anaplasma (marginale) (28), Pseudomonas (stutzeri) (29), and Cowdria (ruminantium) (30). Identical and conserved residues in Cox2p and the Sco homologues are marked by the asterisks. Four of the residues in Cox2p that make contact with the two coppers at the CuA site of subunit 2 are indicated by the arrows. The contact with glutamic acid is at the carbonyl of the peptide backbone (31).
Sco1p could be a mitochondrial copper carrier, accepting copper from
Cox17p and translocating it to the mitochondrial matrix. This model
implies that copper addition to subunits 1 and 2 of the enzyme occurs
on the matrix side of the inner membrane (Fig. 6,
scheme A), perhaps before subunits 1 and 2 of cytochrome
oxidase are fully integrated in the lipid bilayer. Excess Sco1p may
help to correct lesions in Cox17p by increasing the efficiency of
copper uptake from alternate cellular pools. Sco1p could also be a
mitochondrial copper storage and/or transfer protein more directly
involved in addition of copper to the cytochrome oxidase precursor
(Fig. 6, scheme B). Copper need not be transferred across
the inner membrane if addition occurs in the intermembrane space where
the active site of the mature enzyme resides (31). According to this
model also, overexpression of Sco1p could compensate for the absence of
the mitochondrial copper targeting protein by allowing for a more
efficient uptake or transfer of copper during maturation of the
enzyme.
Fig. 6. Possible roles of Sco1p in cytochrome oxidase assembly. Copper imported by the plasma membrane pump (Ctr1p) is transferred to mitochondria via the Cox17p. In mechanism A, Sco1p can function by transporting copper into the mitochondrial matrix compartment where it is used to make the active sites of cytochrome oxidase subunits 1 and 2 (Cox1 and Cox2). Alternatively (mechanism B), copper is transferred from Cox17p to Sco1p in the intermembrane space where it is then used to mature subunits 1 and 2.
Overexpression of Sco2p can partially suppress the respiratory defect of a cox17 point mutant and a strain with a null allele, the latter in the presence of added copper. The activity of SCO2 on a high copy plasmid as an allele-specific suppressor of sco1 mutations could mean that Sco1p and Sco2p exist and function as a complex. Even though the molecular weight of Sco1p and Sco2p is two times the monomer size, no evidence could be obtained for a complex of the two proteins. The dependence of function on such a complex, even if it exists, is also unlikely in view of the absence of a discernable phenotype in the sco2 deletion mutant. An alternative explanation for allele-specific suppression of a sco1 mutation by SCO2 is that the product of this gene is able to provide one of the Sco1p functions lost in the mutant. A redundancy in one of the activities of these two proteins would explain the lack of a phenotype in the sco2-disrupted strain.
FOOTNOTES
Recipient of a Medical Research Council of Canada Post-Doctoral
Fellowship.
§ To whom all correspondence should be addressed. Tel.: 212-854-2920; Fax: 212-865-8246.
1 The abbreviations used are: kb, kilobase pair; bp, base pair.
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