title: Myospryn is a direct transcriptional target for MEF2A that encodes a striated muscle, alpha-actinin-interacting, costamere-localized protein.
abstract: The full repertoire of proteins that comprise the striated muscle Z-disc and peripheral structures, such as the costamere, have yet to be discovered. Recent studies suggest that this elaborate protein network, which acts as a structural and signaling center for striated muscle, harbors factors that function as mechanosensors to ensure coordinated contractile activity. Mutations in genes whose products reside in this region often result in skeletal and cardio myopathies, demonstrating the importance of this macromolecular complex in muscle structure and function. Here, we describe the characterization of a direct, downstream target gene for the MEF2A transcription factor encoding a large, muscle-specific protein that localizes to the costamere in striated muscle. This gene, called myospryn, was identified by microarray analysis as a transcript down-regulated in MEF2A knock-out mice. MEF2A knock-out mice develop cardiac failure during the perinatal period with mutant hearts exhibiting several cardiac abnormalities including myofibrillar disarray. Myospryn is the mouse ortholog of a partial human cDNA of unknown function named cardiomyopathy-associated gene 5 (CMYA5). Myospryn is expressed as a single, large transcript of approximately 12 kilobases in adult heart and skeletal muscle with an open reading frame of 3739 amino acids. This protein, belonging to the tripartite motif superfamily of proteins, contains a B-box coiled-coil (BBC), two fibronectin type III (FN3) repeats, and SPRY domains and interacts with the sarcomeric Z-disc protein, alpha-actinin-2. Our findings demonstrate that myospryn functions directly downstream of MEF2A at the costamere in striated muscle potentially playing a role in myofibrillogenesis.
authors.affiliation: Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Durham
authors.forename: Ondra M
authors.initials: OM
authors.lastname: Brand
authors.forename: Michael
authors.initials: M
authors.lastname: Arnold
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Reynolds
authors.forename: Lavanya
authors.initials: L
authors.lastname: Muthukumar
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
mesh_terms: D000185:Actinin / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012518:Sarcomeres / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C484938:Cmya5 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D000185:Actinin