European Heart Journal Supplements (2002) 4 (Supplement I), I13–I17
Z-line proteins: implications for additional functions
R. Knöll, M. Hoshijima and K. R. Chien
Institute of Molecular Medicine, University of California at San Diego, California, U.S.A.
Z-line proteins have important structural functions. However,
recent publications point to additional, previously unexpected
functions and a new view is now emerging, whereby these
proteins are involved in important intra- and inter-cellular
signaling pathways. Their translocation to the nucleus, the
interaction with other signaling molecules and the ability to
facilitate macromolecular protein complexes indicate the multifunctionality of Z-line proteins. A better understanding of these
emerging physiological roles of Z-line proteins might be
achieved by precise investigations of specific mutations in
specific domains in a subset of these proteins. Clues will be
given to explain the clinical variations in the development and
severity of different forms of cardiomyopathies, which are also
affected by genetic redundancy and ethnic background of
different patient populations.
(Eur Heart J Supplements 2002; 4 (Suppl I): I13–I17)
© 2002 The European Society of Cardiology
Introduction
alpha-actinin interact to establish antiparallel dimers that
are capable of cross-linking actin and titin filaments from
neighbouring sarcomeres[3].
The width of a Z-line can vary from 30 to 160 nm
between different muscle types, suggesting that the
configuration and/or the number of the alpha-actinin crosslinker may differ between muscles[4]. However, Z-line
thickness is also defined by the length of the different Z-line
domains of titin subtypes. In higher vertebrates four
different alpha-actinin genes are present (ACTN1 to
ACTN4); ACTN2 and ACTN3 are specific to striated muscle,
whereas ACTN2 is the cardiac isotype. In addition ACTN3
is absent in approximately 18% of the human population[5].
Disruption of the single alpha-actinin gene in Drosophila
revealed that alpha-actinin is not absolutely necessary for
proper assembly of the contractile machinery, but it is
critical for stabilizing the muscle cytoskeleton once
contraction begins[6]. These observations led to the
hypothesis that other proteins can, at least in part, substitute
for alpha-actinin function during myofibrillogenesis.
A vast majority of cytoskeletal proteins can bind to
different regions of alpha-actinin (for review, see Chien[2]).
Alpha-actinin
Alpha-actinin (Mr = 97 kDa) is one of the major components
of the Z-line. It is a member of the dystrophin superfamily
and contains three different domains: an amino-terminal
actin-binding domain; a central rod domain that is
composed of four spectrin domains; and a carboxylterminal calmodulin-like domain. The rod domains of
Muscle LIM protein
Correspondence: Kenneth R. Chien, University of California at San
Diego, Institute of Molecular Medicine, Basic Science Building
0641, 9500 Gilman Drive, California 92093, USA
1520-765X/02/0I0013 + 05 $35.00/0
The muscle-specific LIM protein (MLP) belongs to a
structurally related superfamily of proteins that harbours
© 2002 The European Society of Cardiology
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The Z-line defines the lateral boundaries of the sarcomere
and anchores thin, titin and nebulin filaments. Because of
these anchoring properties, Z-lines are responsible for force
transmission, generated by the actin–myosin cross-bridge
cycling. However, recent work points to additional, previously
overlooked functions of Z-line proteins, such as signal
transduction and associated nuclear translocation. The
present review summarizes some of the main constituents of
the Z-line, focusing on the emerging new physiological
roles of these structures. For more detailed reviews, see
Chien and Olson[1] and Chien[2].
Key Words: Z-line, DCM, heart failure, cytoskeleton
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R. Knöll et al.
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
downregulation in several different conditions of heart
failure in animal models or in human DCM is a primary
event or whether it is a secondary effect as a consequence of
the deleterious physiological situation. Furthermore, studies
are needed to address the issue of whether normalization of
cardiac function, after therapy, restores MLP expression, or
whether restoration of MLP expression improves cardiac
function.
Four and a half LIM domain proteins
Within the group of LIM proteins several homologous
subgroups of proteins can be distinguished. One of these
groups is characterized by a specific arrangement of
domains, bearing four complete and one amino-terminal
half LIM domains (the FHL family); these proteins are
expressed in a tissue-specific manner and in distinct cellular
compartments. The function of the FHL proteins is not
clear. Recently, members of the FHL family were shown to
behave as transcriptional coactivators. FHL2 has been
reported to enhance the transcriptional activity of the
androgen receptor[16]. Additionally, an isoform of FHL1
known as KyoT2 interacts with recombination signal
binding protein-J, a DNA-binding transcription factor, thus
negatively regulating transcription[17].
FHL2, the first FHL protein to be described, was isolated
by virtue of its being downregulated in rhabdomyosarcoma
cells as compared with their non-malignant equivalents (i.e.
normal human myoblasts)[18]. FHL2 expression is
augmented by transient expression of functional p53 in
rhabdomyosarcoma cells, as well as by endogenous p53
stimulated by ionizing radiation treatment. Moreover, overexpression of FHL2 in both normal and tumour-derived cell
lines efficiently induces an apoptotic programme[19].
Therefore, it is conceivable that FHL2 plays a role in
tumour development and transcriptional regulation in these
cell types. Importantly, FHL2 has been localized at the Zline in cardiac muscle cells[20]. Two independent groups
developed FHL2-deficient mouse models, which resulted
either in no phenotype[21] or in a mild phenotype after betaadrenergic stimulation[22].
Enigma family
The enigma family is a newly emerging family of proteins,
which is defined by an amino-terminal PDZ domain (a
protein interaction module) and one to three carboxylterminal LIM domains[23]. Several family members are
expressed in skeletal muscle and localize at the Z-line,
including enigma[23], actinin-associated LIM protein
(ALP)[24], ENH[25] and cipher[26]. In addition, enigma has
been shown to bind to tropomyosin in skeletal muscle at the
I-band. Z-line targeting is believed to take place via binding
of their PDZ domain to alpha-actinin. Interestingly, ENH,
enigma[25] and cypher bind to protein kinase C[26], and
enigma to the insulin receptor and Ret/ptc[27,28].
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either one or several different LIM domains. (LIM is itself
an acronym that results from the initials of the first three
members of this increasingly growing family of proteins,
namely lin-11, islet-1 and mec-3.) The LIM domain, which
is characterized by the cysteine-rich consensus CX2CX1623HX2CX2CX2CX16-21CX2-3(C/H/D), consists of two
distinct zinc-binding subdomains[7,8]. MLP (Mr = 23 kDa)
belongs to the LIM protein subfamily termed ‘cysteine-rich
protein’ – a group of evolutionarily conserved cytoskeletal
proteins that are prominently expressed in a variety of
muscle tissues[9]. To date more than 60 members of the LIM
protein family have been identified. Detailed reviews
regarding their relevance in disease models have been
published[1,2,10]. Most strikingly, MLP-deficient mice
develop a severe form of dilated cardiomyopathy (DCM)
associated with heart failure, and these mice currently
represent the first genetically engineered organism with this
phenotype[11].
DCM is characterized by dilatation and impaired
contraction of the left ventricle or both ventricles. It may be
idiopathic, familial/genetic, viral and/or immune or alcoholic/
metabolic, or it may be associated with recognized
cardiovascular disease in which the degree of myocardial
dysfunction is not explained by the abnormal loading
conditions or the extent of ischaemic damage. Histology is
non-specific. Presentation is usually with heart failure, which
is often progressive. Arrhythmias, thromboembolism and
sudden death are common and may occur at any stage[12].
In a carefully conducted physiological analysis of MLPnull mice, striking similarities between the human disease
and the mouse MLP knockout heart can be observed. In
addition to the similarities observed between human and
mouse DCMs, MLP gene expression was analyzed in a
series of different experimental settings and in human
explanted hearts. In one study, human explanted idiopathic
dilated cardiomyopathic, ischaemic cardiomyopathic and
non-failing human donor hearts were analyzed for MLP
expression using northern blot and immunoblotting[13].
Surprisingly, there was no difference between the groups
with respect to MLP messenger RNA expression, but there
was a 50%, significant downregulation of MLP protein in
the idiopathic dilated cardiomyopathic hearts and in the
ischaemic cardiomyopathic hearts. In another attempt to
study right ventricular heart failure, induced by pulmonary
hypertension in rats, a marked 50% downregulation of MLP
transcripts were observed[14]. Notably, evidence for a MLP
nuclear relocalization following haemodynamic overload
was present. Furthermore, Ehler et al.[15] reported a MLP
downregulation in another type of DCM, namely the
tropomodulin over-expression transgenic mouse.
Given the fact, that MLP-deficient mice develop a form of
DCM with many of the major features that are present in
humans, a downregulation of MLP in human idiopathic
DCM might be of pivotal importance, implying a basic
mechanism underlying the human condition.
To date it is unknown whether MLP expression underlies
changes in gene expression in other forms of human heart
disease also (i.e. hypertrophic cardiomyopathy, restrictive
cardiomyopathy, congenital cardiomyopathy). It will be
interesting to determine whether the observed MLP
Z-line proteins
Cypher knockout mice exhibit disorganized and disrupted
Z-line structure and die from multiple accounts of striated
muscle failure, including ventricular dilatation, respiratory
distress and severe skeletal muscle weakness[26]. The
skeletal muscle defect is post-natal, indicating that cypher is
not necessary for Z-line assembly but stabilizes this
structure once muscle contraction starts.
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the calsarcin family (together with calsarcin-1, the cardiac
isoform, and calsarcin-3) and binds to calcineurin, a
phosphatase that is involved in the cardiac and skeletal
muscle hypertrophic response. Calcineurin can dephosphorylate and activate NF-AT3, a nuclear transcription
factor that shuttles between nuclei and the cytoplasm.
Interestingly, FATZ binds to cypher also, providing
additional evidence for complex signalling and interactions
at the Z-line[33].
Actinin-associated LIM protein
FATZ family
FATZ, a 32-kDa skeletal muscle protein, is an acronym for
filamin, alpha-actinin, and telethonin-binding protein of the
Z-disc, which indicates its binding partners[30]. Two groups
independently identified this protein and termed it
‘calsarcin-2’[31] and ‘myozenin’[32]. Thus, FATZ belongs to
Myopalladin
Myopalladin, with a molecular mass of about 145 kDa, and
the related ubiquitously expressed protein palladin are
proteins that contain immunoglobulin domains and are
enriched at sites of actin filament anchorage[34]. The
carboxyl-terminal domain is conserved between both
proteins and responsible for its association with alphaactinin. Myopalladin interacts with the SH3 domain of both
nebulin and nebulette via its proline-rich domain, and with
the cardiac ankyrin repeat protein (CARP) within the I-band
via its amino-terminal domain. CARP is a nuclear protein
that is involved in gene expression and was identified by
several independent groups[35,36]. Over-expression of the
amino-terminal myopalladin disrupts Z-line organization
and overall sarcomere structure in chick cardiac myocytes.
This surprising result suggests a connection between
myofibrillar organization and gene expression, probably via
myopalladin interaction with CARP.
Telethonin/T-cap
Telethonin (Mr = 19 kDa), which is also known as T-cap
(Titin cap), binds to the amino-terminal titin domain and
was identified by two independent groups[37,38]. Overexpression of T-cap or the Z1 Z2 amino-terminal titin leads
to disruption of the Z-line and disruption of sarcomere
organization, suggesting an important role for this
interaction, in which T-cap acts as a ‘bolt’ to anchor titin
within Z-lines[38]. In addition, T-cap is believed to be phosphorylated during myofibrillogenesis by the titin kinase[39].
Mutations in T-cap have been reported to be responsible for
forms of human limb–girdle muscular dystrophy[40],
providing additional evidence for the importance of this
gene in Z-line stabilization. Moreover, an interaction
between T-cap and the potassium (IKS) channel beta-subunit
minK was reported. This interaction indicates a Ttubule/myofibril linking system that may link the regulation
of potassium flux and Z-line structure[41].
MURF family
MURF-3 is the founding member of this new family of
cytoskeletal proteins (the acronym ‘MURF’ is derived from
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
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ALP is a 39-kDa protein that consists of one LIM domain
and a PDZ domain; it is expressed in smooth muscle, with
predominant expression in the right ventricular outflow
tract. In the heart the protein is concentrated at the intercalated discs, which form the structural junction between
neighbouring cardiomyocytes, and thus it colocalizes with
vinculin, desmin, alpha-actinin and gamma-catenin (a gene
recently linked with Naxos disease, a form of human
recessive arrhythmogenic right ventricular dysplasia)[29].
ALP promotes cardiomyocyte sarcomeric organization in
isolated neonatal cardiomyocytes and enhances the ability of
alpha-actinin to cross-link F-actin filaments[24]. Targeted
ablation of ALP in a mouse model leads to decreased
trabeculation, irreversible chamber dilatation and dysmorphogenesis of the embryonic right ventricle. Subsequently, adult
mice present with a right ventricular dominant DCM.
The mutation that is present in Naxos disease results in a
truncated form of gamma-catenin, which appears to affect
preferentially right ventricular function. Because gammacatenin is uniformly distributed in both the right ventricular
and left ventricular chambers throughout foetal development and post-natal life, the mechanism for right ventricular
selectivity in Naxos disease in not clear. As gamma-catenin,
vinculin and ALP have all been shown to colocalize with
alpha-actinin at the intercalated disc, the aetiology of the
right ventricular cardiomyopthy might stem from defects in
a macromolecular gamma-catenin/alpha-catenin/alphaactinin/ALP complex at the intercalated discs of ventricular
muscle cells.
In summary, in the ALP knockout mouse model, a
developmental pathway underlies the development of
DCM[24]. With right and mild left ventricular myocardial
dysfunction, thinning of right ventricular walls and loss of
trabeculation, this form of cardiomyopathy resembles many
major features of human right ventricular cardiomyopathies. Therefore, the ALP-null mouse will be useful
for engineering and validation of new therpeutic strategies
designed to target this disease.
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R. Knöll et al.
Table 1 Z-line proteins and corresponding knockout phenotypes
Protein
Knockout phenotype
Muscle-specific LIM protein (MLP)
Cypher
Actinin-associated LIM protein (ALP)
Four and a half LIM domain (FHL)-2
Dilated cardiomyopathy
Congenital myopathy
Right ventricular dominant cardiomyopathy
Either no phenotype or a pronounced hypertrophy after beta-adrenergic stimulation
muscle-specific ring finger). These proteins localize at the
Z-line and at the M-line, but the interacting proteins are not
yet identified[41]. Antisense ablation of MURF-3 expression
in C2 skeletal muscle cells resulted in a severe disruption in
the initiation of myogenesis, indicating a role in
differentiation. In addition, MURF-3-deficient mice display
a myopathic phenotype. The interaction of MURF-3 with
many different binding partners (MURF-1 and MURF-2, Zline proteins, microtubules) indicates that the protein might
function primarily in linking different proteins together.
Conclusion
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
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In summary, there is growing evidence, apart from
mechanical function, for signalling and feedback
mechanisms at the Z-line. In particular, MLP seems to be
involved in different signal transduction pathways and is
thus able to communicate with the nucleus (via its nuclear
localization signal, known nuclear localization, interaction
with myoD?). However, other proteins such as cypher or
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be involved in intracellular signalling also. The known
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binding via over-expression of both components, and the
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importance of the T-cap/titin interaction. The interaction
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Interaction of the amino-terminal myopalladin with CARP
and the known nuclear localization of CARP again point to
another feedback loop between cytoskeletal components
and gene expression. FHL2 also is observed at the Z-line
and in the nucleus, and is known to be involved in gene
expression via its interaction with an androgen receptor.
Another link between the Z-line and gene expression is
represented by calcineurin and the calsarcins. It becomes
increasingly evident that Z-line proteins are able to convey
information from the Z-line to the nucleus and probably
back; that they may be involved in intracellular signaling;
and that they might have additional, yet unknown functions.
It will be of interest to screen patients with distinct phenotypes for mutations in distinct parts of these proteins (i.e.
carboxyl-terminal T-cap domain, interacting with minK; or
the amino-terminal myopalladin domain interacting with
CARP). Another interesting feature of the Z-line proteins is
their redundancy; some knockout models do not have any
phenotype or have only a mild one (FHL2), whereas others
develop a severe phenotype (cypher) that leads to death
shortly after birth and some lead to the development of
cardiomyopathies, similar to the situation in humans (MLP,
ALP; Table 1).
In conclusion, Z-line proteins are multifunctional proteins
and are involved in cellular physiology to a much greater
extent that was previously thought. Knockout animal
models of these proteins resemble human diseases and will
enable us to analyze underlying molecular mechanisms.
Innovative therapeutic strategies and novel drugs can be
designed and their efficacy assessed in such models.
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