Muscle type-specific expression of Zasp52 isoforms in Drosophila

Department of Biology, McGill University, 1205 Dr. Penfield Avenue, Montreal, Quebec, Canada H3A 1B1.
Gene Expression Patterns (Impact Factor: 1.38). 08/2011; 11(8):484-90. DOI: 10.1016/j.gep.2011.08.004
Source: PubMed


Zasp52 is a member of the PDZ-LIM domain protein family in Drosophila, which comprises Enigma, ENH, ZASP, Alp, CLP36, RIL, and Mystique in vertebrates. Drosophila Zasp52 colocalizes with integrins at myotendinous junctions and with α-actinin at Z-disks, and is required for muscle attachment as well as Z-disk assembly and maintenance. Here we document 13 Zasp52 splice variants giving rise to six different LIM domains. We demonstrate stage- and tissue-specific expression in different muscle types for Zasp52 isoforms encoding different LIM domains. In particular, LIM1b is expressed only in heart muscle and certain somatic muscles, implying muscle-specific functions in Z-disk assembly or maintenance.

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Available from: Frieder Schöck, Dec 24, 2013
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    • "Perd is a conserved chondroitin sulfate transmembrane proteoglycan that contains two extracellular laminin G domains and a small intracellular domain with a PDZ-binding consensus sequence, which serves as a linkage to PDZ protein networks. Interestingly, some of the proteins present at the Z-discs that are essential for Z-disc formation and myofibril assembly, such as Zasp52, Zasp66 and Zasp67 proteins, also contain a PDZ domain (Katzemich et al., 2011; Katzemich et al., 2013). Thus, Perd might function by regulating the localization of these PDZ-containing proteins. "
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    ABSTRACT: Muscle differentiation requires the assembly of high-order structures called myofibrils, composed of sarcomeres. Even though the molecular organization of sarcomeres is well known, the mechanisms underlying myofibrillogenesis are poorly understood. It has been proposed that integrin-dependent adhesion nucleates myofibril at the periphery of the muscle cell to sustain sarcomere assembly. Here, we report a role for the gene perdido (perd, also known as kon-tiki, a transmembrane chondroitin proteoglycan) in myofibrillogenesis. Expression of perd RNAi in muscles, prior to adult myogenesis, can induce misorientation and detachment of Drosophila adult abdominal muscles. In comparison to controls, perd-depleted muscles contain fewer myofibrils, localized at the cell periphery. These myofibrils are detached from each other and display a defective sarcomeric structure. Our results demonstrate that the extracellular matrix receptor Perd has a specific role in the assembly of myofibrils and in sarcomeric organization. We suggest that Perd acts downstream or in parallel to integrins to enable the connection of nascent myofibrils to the Z-bands. Our work identifies the Drosophila adult abdominal muscles as a model to investigate in vivo the mechanisms behind myofibrillogenesis.
    Full-text · Article · May 2014 · Journal of Cell Science
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    • "Functionally, LIM domains mediate protein-protein interactions and have diverse cellular roles such as regulators of gene expression, cell adhesion, cell motility and signal transduction. ZASP belongs to the Enigma sub-family and has isoforms with one PDZ domain and either none or three LIM domains [9], [10], [11], whereas in Drosophila Zasp52 has one PDZ domain and six LIM domains [15], [22] and Drosophila Zasp66 has one PDZ domain and another domain [15], [23] with some similarity to the short 26 amino acid region, known as the ZASP-like Motif (ZM) found in some members of the ALP (ALP, CLP-36) and Enigma (ZASP) sub-families of proteins [24], [25]. "
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    ABSTRACT: ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ domain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Drosophila Zasp is spliced even more extensively, with 13 splice variants documented so far (Katzemich et al., 2011). We previously reported that Zasp is involved in the assembly of integrin adhesion sites in Drosophila muscle, that Zasp genetically interacts with aPS2 integrin during muscle attachment, and that in Zasp-deficient flies, embryonic and first larval instar muscles partially detach from myotendinous junctions (Jani and Schöck, 2007). "
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    ABSTRACT: Integrins are heterodimeric adhesion receptors that link the extracellular matrix (ECM) to the cytoskeleton. Binding of the scaffold protein, talin, to the cytoplasmic tail of β integrin causes a conformational change of the extracellular domains of the integrin heterodimer, thus allowing high-affinity binding of ECM ligands. This essential process is called integrin activation. Here we report that the Z-band alternatively spliced PDZ-motif containing protein (Zasp) cooperates with talin to activate α5β1 integrins in mammalian tissue culture and αPS2βPS integrins in Drosophila. Zasp is a PDZ-LIM domain-containing protein mutated in human cardiomyopathies previously thought to function primarily in assembly and maintenance of the muscle contractile machinery. Notably, Zasp is the first protein shown to co-activate α5β1 integrins with talin and appears to do so in a manner distinct from known αIIbβ3 co-activators.
    Full-text · Article · Sep 2012 · Journal of Cell Science
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