1 Departments of Biochemistry and Molecular Biology, Baylor College of Medicine,
Houston, TX 77030, USA
2 Department of Neurology, Baylor College of Medicine, Houston, TX 77030,
USA
* Author for correspondence (e-mail: hepstein{at}bcm.tmc.edu)
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Summary |
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Key words: UCS, Myosin, chaperone, UNC-45, Protein folding
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Introduction |
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The UCS domain family is a group of essential proteins necessary for a
variety of myosin- and actin-dependent functions in eukaryotic organisms from
fungi to nematodes (UNC-45 in Caenorhabditis elegans, CRO1 in
Podospora anserina and She4p in Saccharomyces cerevisiae)
and is also present in additional animal species from Drosophila to
humans. They were originally identified through mutations that disrupt
myosin-dependent processes. Recently, however, C. elegans UNC-45 has
been shown to bind the well-known molecular chaperone Hsp90 and muscle myosin
subfragment-1 (S1) and act as a molecular chaperone for myosin
(Barral et al., 2002).
Here we discuss genetic, biochemical and developmental analyses of UCS proteins in fungi and C. elegans and the exciting new findings that specific isoforms of UNC-45 are present in humans and other vertebrates.
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C. elegans UNC-45 |
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A more detailed genetic analysis of unc-45 revealed recessive
lethal as well as additional temperature-sensitive alleles, demonstrating that
UNC-45 function is essential to C. elegans development
(Venolia and Waterston, 1990).
The lethal unc-45 alleles cause arrest at the two-fold embryonic
stage with a failure to produce functional body wall muscle. This phenotype is
similar to that of mutants lacking the essential myo-3 encoded myosin
heavy chain A, one of the two myosins (A and B) found in C. elegans
body wall muscle thick filaments. Importantly, the temperature-sensitive
alleles directly affect the function of the unc-54-encoded myosin
heavy chain B. Suppression of the phenotype of temperature-sensitive
unc-45 mutants by overproduction of myosin A required a background
null for unc-54 (Venolia and
Waterston, 1990
). This result indicates that myosin B inhibits
assembly of myosin-A-containing filaments in the background of an
unc-45 mutant even though myosin A can functionally substitute for
myosin B (Epstein et al.,
1986
). However, studies of the lethal unc-45 alleles
clearly indicated that UNC-45 also interacts with myosin A and probably the
pharyngeal muscle myosins C and D. The pharynges showed decreased pumping in
all lethal unc-45 alleles whereas the maternally rescuable lethal
allele unc-45(st604) phenotype is enhanced by myosin A overproduction
in contrast to the usual suppression. The st604 mutation has not been
characterized but is probably not a null allele, although the mutation
dramatically reduces its activity. Overproduction of myosin A only enhances
that phenotype by overwhelming the mutant UNC-45, thereby preventing it from
functioning in other myosin-dependent processes. UNC-45 was therefore proposed
to interact directly with all muscle myosins in C. elegans either to
control myosin assembly, organization of thick filaments into arrays or myosin
contractile activity (Venolia and
Waterston, 1990
).
Characterization of the genomic and cDNA sequences encoding UNC-45 provided
significant insights into its function and the unc-45 mutations
(Barral et al., 1998). UNC-45
contains three distinct regions: an N-terminal domain containing three
tetratricopeptide (TPR) repeats, a central region showing only homology to
other animal UNC-45-like proteins and the C-terminal UCS domain, which shares
blocks of sequence identity with fungal UCS proteins and more extensive
homology with the C-terminal regions of other animal UNC-45-like proteins.
Three of the four known temperature-sensitive alleles are associated with
missense substitutions in the UCS domain whereas two lethal alleles contain
stop codons upstream in the central region. The latter produce null mutants
because they prevent translation of much of the central region and the entire
UCS domain and produce a phenotype identical to that observed in
unc-45 knockouts generated by RNA interference
(Venolia et al., 1999
). Since
the temperature-sensitive mutations produce unstable thick filaments
containing scrambled A and B myosins, which normally assemble into distinct
zones within the filament, the UCS domain is directly implicated in thick
filament assembly. It is likely that the scrambled filaments are due to
improperly folded myosin, which is consistent with its lower accumulation
(Barral et al., 1998
). However,
the unc-45 mutation may have also uncovered an assembly function for
UNC-45, and both these possibilities need to be explored further.
Localization of UNC-45 by either antibodies or GFP labeling
(Ao and Pilgrim, 2000;
Venolia et al., 1999
) shows
that it is present in both the body wall and pharyngeal muscles and in the
cleavage furrows of early embryos in C. elegans. In the developing
body wall muscle of early larvae, UNC-45 appears to be cytosolic, whereas in
mature, adult muscle, the protein is clearly localized to the sarcomeric
A-bands that contain thick filaments (Ao
and Pilgrim, 2000
). These results are consistent with the genetic
and molecular studies; moreover, recent two-hybrid analysis suggests that, in
addition to the muscle myosins, cytoskeletal type II and unconventional type V
myosins interact with UNC-45 protein (W. Ao and D. Pilgrim, personal
communication). This interaction with type II myosin is consistent with its
localization to the cleavage furrow since type II myosins are necessary for
the assembly of the contractile ring and its function in cytokinesis
(Balasubramanian et al., 1998
;
De Lozanne and Spudich, 1987
;
Knecht and Loomis, 1987
).
The terminal phenotype of an unc-45 null mutant is at a stage
consistent with a lack of body wall muscle. This stage of arrest is later than
would be expected considering the possible interactions of UNC-45 with myosins
other than those found in body wall muscle and a possible role in cytokinesis
(see S. pombe Rng3p in the next section). However, the null phenotype
can be explained by maternal rescue as has been discussed for its co-chaperone
Hsp90 (Birnby et al., 2000).
Rescue probably occurs at the level of UNC-45 protein because RNA
interference, which generally blocks maternal rescue at the RNA level, when
targeted to UNC-45 produces a muscle-specific phenotype. The maternally
contributed UNC-45 would be enough to fulfill its general cellular functions
but would become overwhelmed when the embryos begin to form muscle
thus the arrest at the twofold stage.
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The fungal UCS proteins |
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She4p of S. cerevisiae
The gene encoding the 789-residue budding yeast protein She4p was
discovered in two independent screens, one for expression of the HO
endonuclease exclusively in mother cells but not buds (the SHE screen
for Swi5p-dependent HO expression) and the other for endocytosis defects (the
dim screen for defective internalization of membrane)
(Jansen et al., 1996;
Wendland et al., 1996
). In
each case, one mutant allele was isolated. Most of the other mutants isolated
were in the SHE1 gene encoding Myo4p, an unconventional type V
myosin. A deletion of the UCS homolog SHE4 leads to decreased growth
and endocytosis, altered cell morphology and loss of actin cytoskeleton
polarity (Jansen et al., 1996
;
Wendland et al., 1996
).
Likewise, the dim1 mutant shows temperature-sensitive loss of
polarity of actin localization, defective secretion and constitutive rounding
of cells. This broad phenotype is consistent with the idea that the mutations
in She4p that occur in DIM1 and SHE4 mutants produce an
intrinsic defect in the actin cytoskeleton and possibly in myosin motor
activity.
CRO1 protein of P. anserina
The CRO1 protein of P. anserina is a 702-residue protein that
shares 21% identity and 40% similarity with She4p. The cro1 gene was
identified through a screen for defects in sexual sporulation. The
cro1-1 allele identified in this screen is a null mutant owing to a
premature chain termination caused by a frame shift mutation. It shows
pleiotropic alterations: abortive meioses leading to polyploid nuclei, an
inability to form septa between the daughter nuclei following mitotic
division, and decreased filamentous growth. In wild type fungal filaments, the
actin assembly is coordinated with microtubule disassembly. However, in the
cro1-1 mutant, the syncytial cytoplasm becomes filled with multiple
nuclei and the actin cytoskeleton becomes disorganized, which permits abundant
microtubules to remain (Berteaux-Lecellier
et al., 1998). In the absence of CRO1 function, myosins that
interact with and organize the actin cytoskeleton may not be functional and as
a result, the signaling pathway that regulates actin assembly and microtubule
disassembly is disrupted. This pathway may be similar to one in S.
pombe that monitors the integrity of the actin cytoskeleton and delays
sister chromatid separation until the mitotic spindle is properly oriented
(Gachet et al., 2001
).
Rng3p of S. pombe
The RNG3 gene was identified in a screen for defective actomyosin
ring assembly and cytokinesis in S. pombe cell division
(Balasubramanian et al., 1998).
Missense mutations in the UCS domain of the predicted 746-residue protein
generate several temperature-sensitive mutants
(Wong et al., 2000
). When
these were crossed specifically with myo2 mutants (myo2
encodes the essential myosin heavy chain of the actomyosin cytokinetic ring),
synthetic lethals resulted, which suggests at least functional interaction
between the two proteins. The rng3 null mutant fails to undergo
cytokinesis, generating spores with multiple nuclei. In addition, it exhibits
defective actin organization and actomyosin ring assembly. Perhaps most
significantly, the specific myo2-E1 mutant, in which there is a G345R
substitution in the Myo2p motor domain, causes sequestration of wild type Rng3
protein in the defective actomyosin ring. None of the other myosin mutants or
other cytokinetic-defective mutants does this, which suggests that there is a
specific interaction between the E1 mutant motor domain of Myo2p and Rng3p. In
interphase, myosin forms a `spot' that is the putative progenitor to the
cytokinetic actomyosin ring. The maintenance of this spot requires the
function of Rng3p and this spot is proposed to be a template upon which the
actomyosin ring forms during cytokinesis
(Wong et al., 2002
). Rng3p may
be necessary for maintaining the myosin in an assembly-competent state and
therefore act in a manner similar to UNC-45 during the assembly of body wall
muscle thick filaments.
The fungal UCS proteins SHE4, CRO1 and RNG3 all show sequence similarity in their C-terminal UCS domains to UNC-45, but the phenotypes of their mutants show few significant similarities. However, all three fungal UCS genes and unc-45 are linked by their common association with processes related to or requiring myosins (Fig. 2). These results provide additional evidence for UCS proteins acting not strictly on conventional myosins but on unconventional myosins as well and suggest that they may have a more general function in the cell.
Molecular studies of UNC-45
Unlike its fungal relatives, UNC-45 contains three predicted domains
including the conserved UCS domain that interacts functionally with various
myosins (Fig. 2)
(Barral et al., 1998). The
N-terminal TPR domain, not present in the fungal proteins, resembles those
that interact with the molecular chaperones Hsp70 and Hsp90 while the central
domain shows sequence similarity only to other animal UCS proteins. Several
recombinant proteins have been constructed to test for protein-protein
interactions.
Recombinant full-length UNC-45 protein (FL) forms a complex with Hsp70,
Hsp90 and body wall muscle myosin (Fig.
3). Hsp70 and Hsp90 in Sf9 insect cells and C. elegans
lysates and myosin in high salt extracts of C. elegans are pulled
down by UNC-45 [(Barral et al.,
2002); A. H. Hutagalung, J. M. Barral and H. F. Epstein,
unpublished].
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An UNC-45 construct lacking the TPR domain [TPR(-)] binds to myosin and
possess general chaperone activity. Purified C. elegans myosin binds
to purified Hsp90, full-length UNC-45 and TPR(-) and this interaction occurred
at 30°C but not at 4°C (Barral et
al., 2002). This is similar to the interaction of Hsp90 and its
associated co-chaperones with client proteins such as the steroid receptors
(Dittmar and Pratt, 1997
;
Kosano et al., 1998
). The
elevated temperature promotes hydrophobic interactions consistent with UNC-45
and Hsp90 acting as molecular chaperones for myosin.
The TPR domain of UNC-45 binds the conserved C-terminal MEEVD sequence of
Hsp90 (Fig. 3). This sequence
has been shown by crystallographic and binding studies to be sufficient in
distinguishing between TPR domains that bind Hsp90 and those that bind Hsp70
(Scheufler et al., 2000). In
pull-down experiments, full-length UNC-45, but not the TPR(-) UNC-45
construct, associates with Hsp90. Furthermore, surface plasmon resonance
experiments indicate that Hsp90 directly binds recombinant TPR domain, and
this interaction is blocked most efficiently by peptides corresponding to the
C-terminus of Hsp90 but not that of Hsp70 or non-specific peptides
(Barral et al., 2002
).
Both full-length UNC-45 and the TPR(-) construct, but not the TPR domain
alone, show biochemical chaperone activity
(Fig. 3) towards the general
chaperone substrate citrate synthase (CS). They protect CS against thermally
induced aggregation, which occurs at concentrations of UNC-45 that are
substoichiometric to CS. In addition, they enhance the renaturation of
thermally inactivated CS when the reactions are incubated with one of its
substrates, oxaloacetate (Barral et al.,
2002).
UNC-45 protein binds directly to myosin S1, or the myosin head, which
contains the motor domain, and functions as a chaperone for S1 by preventing
its thermally induced aggregation (Fig.
3) (Barral et al.,
2002). This result thus explains the specific sequestration of
Rng3p by the myosin motor domain mutation E1 in the myo2 cytoskeletal
type II myosin heavy chain of S. pombe described above
(Wong et al., 2000
). Yeast
two-hybrid experiments show that C. elegans UNC-45 can bind to C.
elegans NMY-2 cytoskeletal and HUM-2 type V myosin heavy chains (W. Ao
and D. Pilgrim, personal communication). These independent results suggest
that the most likely targets of the UCS proteins are the shared motor domains
of the different isoforms and classes of myosin and that facilitation of the
folding of these domains, rather than purely assembly of myosins, is the most
general function of UCS proteins.
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Problems and successes in myosin folding |
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Expression of myosin motor domains as either S1 or heavy meromyosin (HMM,
Fig. 4) fragments leads to very
different results, even with co-expression of the light chains. To date,
neither muscle nor non-muscle (cytoskeletal) myosin heads can be expressed as
functional proteins in bacteria (McNally
et al., 1988; Mitchell et al.,
1986
). The ability to express recombinant proteins through
baculovirus infection of insect cells has permitted expression of HMMs derived
from cytoskeletal and smooth muscle type II, V and VI myosins that are soluble
and exhibit motor activity (Sweeney et
al., 1998
; Wang et al.,
2000
; Wells et al.,
1999
). However, neither cardiac nor skeletal muscle sarcomeric
myosin HMMs can be obtained in soluble form from these cells (H. L. Sweeney
and J. R. Sellers, personal communication). Two hypotheses can explain these
results. First, bacteria lack additional eukaryotic factors required for the
proper folding of the motor domains of several classes of cytoskeletal
myosins. Second, non-striated muscle eukaryotic cells lack but striated muscle
cells produce additional factors specifically required for the proper folding
of sarcomeric myosin heads. Indeed, the folding of chicken skeletal muscle HMM
in rabbit reticulocyte lysates is enhanced by a muscle-derived extract and
muscle cells, but not kidney epithelial cell lines, produce functional
recombinant skeletal muscle myosin
(Srikakulam and Winkelmann,
1999
; Chow et al.,
2002
).
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Vertebrates express general cell and striated muscle UNC-45 isoforms |
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The complete genomes of C. elegans, Drosophila melanogaster and
the mosquito Anopheles gambiae appear each to contain only one UNC-45
gene. The appearance of a second UNC-45 gene may have ancient roots in
vertebrate radiation that occurred possibly during bony fish evolution
(Fig. 5). We identified
putative GC and SM UNC-45 gene products in the genome of the pufferfish
Fugu rupbripies on the basis of their 64% and 72% identities to the
respective verified mammalian isoforms.
(Price et al., 2002). In
common with their mammalian counterparts, the two potential fish isoforms
share only 54% identity. As the complete genomes of other vertebrates and
chordate ancestors become available, it will be possible to identify when the
second gene evolved.
|
All animal UNC-45 proteins have the three-domain structure found in C.
elegans UNC-45: an N-terminal TPR domain, a unique central region and a
C-terminal UCS domain. Blocks of homology within each region are maintained
throughout the entire vertebrate and invertebrate proteins. The largest
conserved block, LVGLCK, is near the end of the central region. Such conserved
blocks are even larger if one considers only vertebrate species. The sites of
mutations demonstrated in C. elegans and S. pombe UCS
domains are identical or conserved throughout all identified homologues
(Barral et al., 1998;
Wong et al., 2000
).
The two mouse UNC-45 isoforms are differentially expressed in development.
At 9-11 days of murine embryonic development, the GC isoform mRNA is most
prominently seen in the branchial arches, and the SM isoform mRNA is chiefly
expressed in the heart (Price et al.,
2002).
In C2C12 myogenic cell development in vitro, only the GC isoform mRNA is
detected in proliferating myoblasts whereas SM mRNA is first detected during
cell fusion and becomes the predominant isoform during myotube maturation.
Antisense oligonucleotides to the GC isoform inhibit myoblast proliferation
and fusion whereas antisense to the SM isoform appears to have its greatest
effect upon sarcomere organization (Price
et al., 2002). These results suggest that the GC isoform plays a
role predominantly in cytoskeletal motility and the SM isoform specifically
functions in myogenic processes, including sarcomeric thick filament assembly.
Whether the two isoforms have distinct intrinsic functions or whether their
different roles are determined by their differential expression is not yet
clear and further experiments will be required to answer this question.
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Targeted chaperone systems |
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Conclusions and perspectives |
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Acknowledgments |
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