From the Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1101
The dystrophin-glycoprotein complex
(DGC)1 is a multimeric
transmembrane protein complex first isolated from skeletal muscle membranes (1). The central protein of the DGC is dystroglycan (Fig.
1). In addition to skeletal muscle,
dystroglycan is strongly expressed in heart and smooth muscle, as well
as many non-muscle tissues including brain and peripheral nerve. In
vertebrates, dystroglycan is generated from a single gene
(DAG1), which is cleaved into a peripheral
INTRODUCTION
TOP
INTRODUCTION
Post-translational Processing...
Post-translational Disruption...
Insights into Dystroglycan...
Perspective
REFERENCES
-dystroglycan
protein and a transmembrane
-dystroglycan protein (2). At the
sarcolemma in muscle,
-dystroglycan binds intracellularly to
dystrophin, which binds the actin cytoskeleton, and extracellularly to
-dystroglycan.
-Dystroglycan completes the link from the
cytoskeleton to the basal lamina by calcium-dependent binding with high affinity to extracellular matrix proteins (Fig. 1)
containing LamG domains, such as laminin (3), neurexin (4), agrin
(5-8), and perlecan (9). In addition to dystroglycan and dystrophin,
the DGC in muscle cells contains a sarcoglycan complex composed of four
sarcoglycan proteins (
,
,
,
) and sarcospan (1, 10).
Intracellularly, the sarcolemma DGC, through dystrophin, interacts with
a pair of syntrophins (
1 and
1) (11) and
-dystrobrevin (12).
-Syntrophin and
-dystrobrevin can interact with nNOS and localize
it to the sarcolemma (13, 14). Syntrophin also can interact with
aquaporin 4 through a PDZ domain and can stabilize it in the sarcolemma
(15). The C-terminal tail of
-dystroglycan also contains a
PPXY motif that can interact with dystrophin or caveolin 3 (16). The exact function of the entire DGC is not completely determined
but it is thought to contribute to the structural stability of the
muscle cell membrane during cycles of contraction and relaxation (17).
In humans, mutations in dystrophin cause Duchenne and Becker muscular
dystrophy, mutations in sarcoglycans in skeletal muscle cause
limb-girdle muscular dystrophy, and mutations in
2 laminin cause
congenital muscular dystrophy (18). Despite the central role of
dystroglycan in the DGC, no primary mutations in dystroglycan have been
identified in any human disease. However, mutations in dystrophin do
cause a secondary reduction in sarcolemma expression of dystroglycan (2). Disruption of the DAG1 gene in mice results in embryonic lethality, and dystroglycan appears essential for the formation of the
basement membrane (Reichert's membrane) that separates the embryo from
the maternal circulation in the mouse (19, 20).
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Fig. 1.
The muscle dystrophin-glycoprotein
complex. The components of the core dystrophin-glycoprotein
complex that co-purify in a large molecular mass complex from
digitonin-solubilized skeletal muscle membranes are shown. Proteins
that may form an association with proteins in this complex but have not
been shown to purify with the complex are in yellow. The
ligands for dystroglycan are shown in green.
Emerging genetic data have shown that mutations in proteins with
homology to glycosyltransferases are linked to murine and human
muscular dystrophies. Biochemical analysis of muscle biopsies has
revealed a convergent role for these proteins in the glycosylation of
-dystroglycan, a process that is required for its functional activity. The loss of dystroglycan function by incomplete glycosylation can lead to a variety of clinical symptoms including muscular dystrophy
and abnormal central nervous system development and function. Here we
review what is known about the biosynthetic pathway of dystroglycan
required for its normal structure and function and the new insights
into dystroglycan function revealed from the study of mouse models and
human patients with incomplete glycosylation-induced
"dystroglycanopathies." Because the only detected DGC defect in
these "dystroglycanopathies" is the disruption of the dystroglycan
ligand binding domain, the recent work supports the proposal that the
functions of components of the DGC in the sarcolemma of differentiated
skeletal muscle are largely to support the integrity and sarcolemma
localization of the central extracellular matrix receptor, dystroglycan.
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Post-translational Processing and Structure of Dystroglycan |
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An N-terminal signal peptide directs insertion of dystroglycan
into the endoplasmic reticulum membrane with the N terminus in the
lumen (Fig. 2A). Dystroglycan
is then cleaved by an unidentified protease at amino acid 653 into the
- and
-dystroglycan subunits (2, 21). The significance of this
cleavage is unknown, particularly because the amino acid sequence
around the cleavage site in vertebrate dystroglycan is not conserved in
Caenorhabditis elegans and Drosophila melanogaster, and Western blotting with a C-terminal antibody suggests that the dystroglycan peptide is not cleaved into two subunits
in Drosophila (22). N-Linked and full
O-linked glycosylation and plasma membrane trafficking of
dystroglycan are not required for cleavage of dystroglycan, suggesting
that it may occur in the endoplasmic reticulum (23, 24). The C-terminal
region of
-dystroglycan (residues 550-585) binds to the N terminus
of
-dystroglycan (residues 654-750) independently of glycosylation (25). The sarcoglycan complex also appears to be required for a strong
interaction of
-dystroglycan with the DGC in skeletal muscle.
Sarcoglycan-null mutations, resulting in the loss of the sarcoglycan
complex, result in dissociation of
-dystroglycan from muscle
membranes and the DGC (10).
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Dystroglycan undergoes N-linked and extensive
O-linked glycosylation, which causes -dystroglycan to
migrate on SDS-PAGE as a broad band with an approximate molecular mass
of 120-180 kDa depending on tissue type (156 kDa in muscle, predicted
molecular mass is ~75 kDa) (2).
-Dystroglycan contains a large
mucin-like domain with a number of Ser or Thr residues, which are
potential sites for O-glycosylation (2). Dystroglycan also
contains four potential N-linked glycosylation sites, three
in
-dystroglycan and one in
-dystroglycan (2). Exhaustive
treatment of dystroglycan with N-glycanases does not alter
its activity as an extracellular matrix receptor suggesting that
N-linked sugars are not required for ligand binding (3).
However, full chemical deglycosylation of dystroglycan results in the
complete loss of ligand binding activity (3). Interestingly, the same
chemical deglycosylation also results in the loss of reactivity of two
monoclonal antibodies raised against dystroglycan, clones IIH6 and
VIA41 (3). IIH6 antibody inhibits laminin binding, suggesting that
O-linked sugars are required for both ligand binding and the
reaction of these monoclonal antibodies with dystroglycan (3). The
O-linked glycoconjugates contain a fairly unique sugar
linkage where mannose is directly coupled to serine or threonine in the
dystroglycan peptide (26, 27). This O-mannosyl linkage has
only been found in a few other mammalian proteins (28). In peripheral
nerve dystroglycan, this Neu5Ac(
2-3)Gal(
1-4)GlcNAc(
1-2)Man-Ser/Thr glycoconjugate
has been proposed to be required for laminin binding (26). However, millimolar concentrations of this glycoconjugate are required to
competitively inhibit laminin binding to dystroglycan (26). Sialic acid
has also been reported to competitively inhibit laminin binding to
peripheral nerve dystroglycan at lower concentrations than the above
glycoconjugate (29). However, enzymatic removal of sialic acid from
skeletal muscle dystroglycan has no effect on laminin binding (30).
Furthermore, dystroglycan from brain and cardiac muscle has decreased
terminal sialoglycosylation compared with skeletal muscle dystroglycan,
but dystroglycan from all three tissues binds tightly to laminin (30).
Therefore, although it is well accepted that glycoconjugates are indeed
important for ligand binding, the hypothesis that specific
glycoconjugates on dystroglycan are involved directly in ligand binding
is still controversial.
The extensive glycosylation of dystroglycan has made the
elucidation of the structure of the peptide and glycoconjugates and the
generation of peptide antibodies technically challenging. Rotary
shadowing and electron microscopy of purified chick -dystroglycan showed dumbbell-shaped particles with two globular domains linked by a
flexible segment (31). Presumably, the flexible linker domain
corresponds to the mucin domain extended by the large number of
attached glycoconjugates. The crystal structure of the C terminus of
dystrophin with a
-dystroglycan peptide has revealed that an EF hand
domain in dystrophin stabilizes an interaction of a WW motif
(PPXY) in the C-terminal tail of
-dystroglycan with a WW
domain in dystrophin (32). The crystal structure of the
2 laminin
G-domains reveals that a coordinated calcium ion is surrounded by a
basic surface that is thought to provide the site for interactions with
acid glycoconjugates (such as sialic acid) on dystroglycan (33). How
this structural surface on the G-domain confers a specific interaction
with dystroglycan and not with other sialic acid-containing
glycoproteins is not clear. The complete enzymatic pathway for
dystroglycan processing, the exact binding site for ligands on
dystroglycan, and the direct or structural role of dystroglycan
glycoconjugates in ligand binding activity is still not determined.
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Post-translational Disruption of Dystroglycan Function in Muscular Dystrophy |
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Despite the fact that mutations in dystroglycan in humans have not
been found, recent studies have indicated, rather surprisingly, that
the dystroglycan post-translational processing pathway is a convergent
target for many human muscular dystrophies (supplemental Table
I). Fukuyama congenital muscular
dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg
Syndrome (WWS) are severe congenital muscular dystrophies with mental
retardation, neuronal migration defects including cobblestone
lissencephaly, and variable ocular anomalies (MEB and WWS) (34). The
FCMD gene mutation was first identified as a retrotransposon insertion
into the fukutin gene (35). The function of fukutin is
unknown, but the protein has homology to the fringe-like
family of enzymes that modify glycolipids and glycoproteins (36). More
recently, the gene responsible for MEB was identified as an
O-mannosyl-1,2-N-acetylglucosaminyltransferase (POMGNT1)(37). A homologue for fukutin was also
identified in humans, termed fukutin-related protein (FKRP),
and is mutated in a form of congenital muscular dystrophy and a milder
dystrophy, limb-girdle muscular dystrophy 2I (LGMD2I) (38, 39).
The identification of dystroglycan as the post-translational target
responsible for the phenotype in these enzyme disorders originated
largely from the study of human patient muscle biopsies. A few
preliminary reports had suggested that -dystroglycan was missing in
the muscle fiber membrane in MEB and FCMD (40, 41). However, recent
data convincingly show in MEB and FCMD muscle that core
-dystroglycan protein and the entire DGC are present at the
sarcolemma, but
-dystroglycan is shifted in molecular mass by ~60
kDa (24). The apparent altered post-translational modification of
-dystroglycan results in the absence of epitopes for the monoclonal
antibodies, IIH6 and V1A41, similar to the chemical deglycosylation
experiments performed by Ervasti and Campbell (3). Based also on
findings of mutations in POMGNT1 in the MEB patients (24),
this shift can be attributed to abnormal O-mannosyl
glycosylation of
-dystroglycan. This hypoglycosylation causes
-dystroglycan to be non-functional as a receptor for its known
extracellular matrix proteins, including laminin, neurexin, and agrin
(24). Interestingly, sarcolemma glycoproteins prepared by lectin
chromatography (that also enriched both normal and mutant dystroglycan)
revealed an almost complete loss of total high affinity laminin binding
activity, suggesting that dystroglycan is one of the major glycoprotein
laminin receptors in human muscle sarcolemma (24). Because mutations in
laminin
2 (42) and dystrophin (43) also cause muscular dystrophy,
the muscle phenotype is likely due to a similar loss of the functional
link across the sarcolemma by dystroglycan from dystrophin to laminin.
However, a major question remained whether dystroglycan was responsible
for the neuronal migration phenotype in human patients. A mutation in
the spontaneous mutant myodystrophy (myd) mouse was
identified by positional cloning in the gene LARGE, which also encodes a putative glycosyltransferase (44). Despite more than 25 years since the identification of the myd mutant mouse, no
brain phenotype had been described (45). Careful examination of the
brains of the myd mice revealed abnormal glycosylation of
-dystroglycan leading to the functional loss of ligand binding activity similar to myd skeletal muscle, abnormal cerebral
cortical layering resembling human cobblestone lissencephaly, and
defects in cerebellar granule cell migration (24). Because a number of
proteins could be targeted by this enzymatic pathway, it was still
unclear if the functional defect in
-dystroglycan was sufficient to
account for the brain phenotype. Using cre-LoxP gene targeting, the
dystroglycan gene was deleted in the mouse brain, and the abnormal
neuronal migration closely mimicked the myd mouse and resembled lissencephaly seen in FCMD, MEB, and WWS patients (46). The
very recent identification of the human WWS gene as a putative O-mannosyltransferase (POMT1) and the
demonstrated loss of glycosylated
-dystroglycan epitopes in WWS
muscle biopsies (47) suggests that MEB, WWS, FCMD, and myd
muscle and brain phenotypes can be explained by a loss of function of
-dystroglycan due to abnormal glycosylation.
Likely, not all the genes participating in this -dystroglycan
processing pathway have been identified, and mutations in these genes
may be responsible for unexplained forms of muscular dystrophy and
diseases of abnormal neuronal migration (Fig. 2B). In
patients with FKRP mutations, no developmental brain
phenotype is apparent (38, 39) suggesting that another enzyme(s) might
compensate for FKRP activity in brain. This also raises the intriguing
possibility that enzymes involved in glycosylating dystroglycan
specifically in brain may be responsible for unexplained forms of human
lissencephaly without muscular dystrophy. The variable eye pathology in
MEB, WWS, and FCMD (largely absent in the latter syndrome) suggests there may be additional genes or targets for these pathways in the eye.
In the recent report on WWS patients, only 5 of 13 patients had
mutations in POMT1 suggesting that additional unidentified enzymes may be required for dystroglycan glycosylation in these patients (47). myd mice also escape the embryonic lethality seen in dystroglycan knock-out mice suggesting a potential
developmentally regulated compensatory enzyme for LARGE. The
POMT1 gene is a homologue of rotated abdomen in
Drosophila (48). Rotated abdomen mutants show
defects in myogenesis (49), although it has not been demonstrated that
this phenotype is caused by a defect in Drosophila
dystroglycan. Finally, the cellular biology and enzymatic activities of
fukutin, FKRP, POMT1, and LARGE have not been experimentally
determined. Surprisingly, mutations in LARGE and
fukutin cause a similar molecular mass shift (~60 kDa) of
-dystroglycan as observed in MEB patients (24). This suggests that
LARGE and fukutin may interact with POMGNT1 or POMT1 by supplying
precursor sugars or directly modulating their enzymatic activity (Fig.
2B).
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Insights into Dystroglycan Function from Human Patients and Mouse Models |
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The studies of -dystroglycan post-translational
processing in human patients and mouse models have revealed important
new insights into the function of dystroglycan and the DGC. Although the genetic role of the DGC in muscular dystrophy is well established, the functional role of dystroglycan in skeletal muscle is still debated. Because dystroglycan is important for assembly of Reichert's membrane in developing embryos (19, 20), it was hypothesized that
skeletal muscle basement membranes would be severely disrupted when
dystroglycan was functionally or genetically disrupted. However, despite large disruptions of basement membrane and matrix protein isoform expression in myd mouse brains, the skeletal muscle
basement membranes in myd mice are morphologically intact
with normal matrix protein isoform expression and localization (24).
Muscle basement membrane formation is also normal when the dystroglycan
gene is specifically targeted in muscle (50). This suggests that
dystroglycan may not be essential as a basement membrane organizer in
muscle, and additional matrix receptors may partially compensate for
the functional loss of dystroglycan. Integrins containing
1 isoforms are also required in concert with
dystroglycan for complete embryonic basement membrane assembly (51-53)
and may in part compensate for the loss of dystroglycan as a basement
membrane organizer in muscle (54, 55).
The function of dystroglycan in muscle has also been examined by specific genetic targeting of the DAG1 gene in mice. Chimeric mice generated from targeted embryonic stem cells showed that the genetic reduction of dystroglycan expression in muscle could cause muscular dystrophy (56). Similar to myd mice, muscle basement membrane formation was morphologically normal in dystroglycan-null chimeric mice (56). In addition, although dystroglycan may still play an important role as an agrin receptor in the development of the neuromuscular junction, dystroglycan expression is not required for initial formation of this sarcolemma specialization in response to agrin (57, 58). More recently, the DAG1 gene was targeted by cre-LoxP technology in differentiated skeletal muscle and resulted in normal muscle basement membrane formation but a surprisingly mild dystrophic phenotype (50). The creatine kinase promoter used to express cre-recombinase in these studies failed to target dystroglycan expressed in satellite cells, and aged mice displayed a remarkable ability to continue to regenerate muscle compared with other DGC-associated dystrophic mouse models (50). This suggests that dystroglycan may play an important role in satellite cell survival or function. Interestingly, muscle biopsies from human patients with a dystroglycan post-translational processing defect and mild limb-girdle muscular dystrophy were also examined (most likely LGMD2I, although not determined in this study). These patients showed a similar expression pattern of residual normally processed dystroglycan from satellite cells after regeneration (50). This could be explained by an additional satellite cell-enzyme that compensates for the mutant enzyme in these LGMD patients, but the expression of the enzyme turns off as the myoblasts differentiate during the regeneration process. This phenomenon of residual normal dystroglycan expression from regenerating satellite cells is not demonstrated in the severe muscular dystrophies of myd mice and FCMD or MEB patients (24). Therefore, precise understanding of the dystroglycan processing pathway and its developmental regulation may shed important light into how dystroglycan modulates satellite cell function and how dystroglycan processing might be targeted therapeutically to increase functional dystroglycan expression, promote muscle regeneration, and improve the dystrophic phenotype.
Despite the loss of laminin binding activity of dystroglycan in
myd, FCMD, and MEB muscle, the remaining DGC proteins can still localize to the sarcolemma (24). Also, dystrophin and dystrophin-associated proteins can still localize to the
sarcolemma after the genetic deletion of the entire dystroglycan
protein in muscle (50, 59). In contrast, the abnormal glycosylation of
-dystroglycan in myd mouse brain causes the failure of
targeting of many normally expressed DGC-related proteins, including
dystrophin, to neural synapses and glial end feet (24). For muscle,
this suggests the DGC may be targeted to the sarcolemma either by a stronger association with the actin cytoskeleton through the 400-kDa skeletal muscle dystrophin isoform, or perhaps an additional sarcolemma protein that stabilizes dystrophin or the DGC at the sarcolemma. In
brain, dystroglycan, specifically by its ability to bind ligands, has a
unique scaffold function to recruit proteins associated with the DGC to
the localized structures with glia and neurons. It is still unknown
which molecules are targeted to the synapse by dystroglycan, which
ligands are important, and if those molecules are directly responsible
for the functional synaptic defect in brain-specific dystroglycan
knock-out mice (46). It is tempting to speculate that the failure of
recruiting functional molecules to the synapse by dystroglycan and
dystrophin may in part underlie the cognitive impairment in FCMD, MEB,
WWS, and a subset of dystrophin-associated muscular dystrophies (34,
60).
The finding that the DGC proteins can still localize to the sarcolemma
in dystroglycan glycosylation-deficient muscular dystrophies (24, 50,
59) also sheds new light on how the entire DGC may function. Several
studies in mouse models of DGC-associated muscular dystrophies have
attempted to assign a signaling molecule scaffold function to the DGC
or direct roles of functional molecules associated with the DGC (such
as aquaporin 4 and nNOS) in the pathogenesis of muscular dystrophy
(reviewed in Refs. 61 and 62). However, in the abnormal glycosylation
dystroglycanopathies, dystroglycan, the DGC, and associated proteins
are correctly targeted to the sarcolemma. Only the extracellular ligand
binding domain of -dystroglycan is disrupted, and muscular dystrophy
still develops. Therefore, the functional roles of the DGC proteins,
such as the sarcoglycans and to some extent dystrophin, in relationship
to dystroglycan, may be more similar to the relationship of structural accessory proteins to the pore-forming subunits of ion channels. Sarcoglycans may function primarily to stabilize the dystroglycan
and
subunit interactions (10), and dystrophin provides cytoskeleton interactions to stabilize and target dystroglycan to the sarcolemma. Dystroglycan, as the central component, contributes an important function as a ligand receptor and adhesive protein that helps stabilize
the sarcolemma relative to the extracellular matrix. The lack of an
essential signaling role of the DGC-associated proteins would be
consistent with a lack of muscular dystrophy phenotype in aquaporin
4-null, nNOS-null, and syntrophin-null mutations in mice that
dissociate or remove nNOS from the sarcolemma (13, 63, 64). The
function of
-dystrobrevin as a cytoplasmic protein of the DGC in
this hypothesis is less certain, because dystrobrevin-null mice have
normal DGC and dystroglycan localization to the sarcolemma but still
have a very mild myopathy (14). However, because dystrobrevin isoforms
can interact with dystrophin (12) and sarcoglycans (65), it remains to
be tested whether or not dystrobrevin may indirectly destabilize the
-dystroglycan association with the DGC resulting in a partial
phenotype (i.e. by altering sarcoglycan function) without
modulating the sarcolemma DGC localization.
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Perspective |
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In summary, the work over the last 10 years on the biochemistry of
dystroglycan and its interaction with ligands and the development of
specific antibody reagents allowed for the identification of the
mechanism causing several inherited human muscular dystrophies. In
turn, the genetic data on human patients and mutant mice are identifying the important players in the basic biology of the O-mannosylation pathway that is required for dystroglycan
function. With the combination of appropriate genetic modeling in mice, the full circle is being completed to fully understand the enzymatic processing and function of dystroglycan in muscle and non-muscle tissues. Hopefully, through this work, appropriate therapeutic targets might be revealed to restore normal dystroglycan processing and/or function to prevent the development of dystroglycan-associated diseases.
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FOOTNOTES |
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* This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. The recent work from these authors' laboratory summarized here was supported in part by the Muscular Dystrophy Association. This is the fourth article of four in the "Skeletal Muscle Basement Membrane-Sarcolemma-Cytoskeleton Interaction Minireview Series."
The on-line version of this article (available at
http://www.jbc.org) contains Table I and Refs. 75 and 76.
Supported by a Cardiovascular Interdisciplinary Research
Fellowship and a University of Iowa Biosciences Initiative Fellowship.
§ Investigator for the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Institute, 400 EMRB, University of Iowa, Iowa City, IA 52242-1101. Tel.: 319-335-7867; Fax: 319-335-6957; E-mail: kevin-campbell@uiowa.edu.
Published, JBC Papers in Press, January 29, 2003, DOI 10.1074/jbc.R200031200
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ABBREVIATIONS |
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The abbreviations used are: DGC, dystrophin-glycoprotein complex; nNOS, neuronal nitric-oxide synthase; FCMD, Fukuyama congenital muscular dystrophy; MEB, muscle-eye-brain disease; WWS, Walker-Warburg Syndrome; FKRP, fukutin-related protein; LGMD, limb-girdle muscular dystrophy.
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