title: Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP) mutations in the actin-binding domain cause disruption of skeletal muscle actin filaments in myofibrillar myopathy.
abstract: The core of skeletal muscle Z-discs consists of actin filaments from adjacent sarcomeres that are cross-linked by α-actinin homodimers. Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP)/Cypher interacts with α-actinin, myotilin, and other Z-disc proteins via the PDZ domain. However, these interactions are not sufficient to maintain the Z-disc structure. We show that ZASP directly interacts with skeletal actin filaments. The actin-binding domain is between the modular PDZ and LIM domains. This ZASP region is alternatively spliced so that each isoform has unique actin-binding domains. All ZASP isoforms contain the exon 6-encoded ZASP-like motif that is mutated in zaspopathy, a myofibrillar myopathy (MFM), whereas the exon 8-11 junction-encoded peptide is exclusive to the postnatal long ZASP isoform (ZASP-LΔex10). MFM is characterized by disruption of skeletal muscle Z-discs and accumulation of myofibrillar degradation products. Wild-type and mutant ZASP interact with α-actin, α-actinin, and myotilin. Expression of mutant, but not wild-type, ZASP leads to Z-disc disruption and F-actin accumulation in mouse skeletal muscle, as in MFM. Mutations in the actin-binding domain of ZASP-LΔex10, but not other isoforms, cause disruption of the actin cytoskeleton in muscle cells. These isoform-specific mutation effects highlight the essential role of the ZASP-LΔex10 isoform in F-actin organization. Our results show that MFM-associated ZASP mutations in the actin-binding domain have deleterious effects on the core structure of the Z-discs in skeletal muscle.
authors.affiliation: From the Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892-3075.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lin
authors.forename: Janelle
authors.initials: J
authors.lastname: Ruiz
authors.forename: Ilda
authors.initials: I
authors.lastname: Bajraktari
authors.forename: Rachel
authors.initials: R
authors.lastname: Ohman
authors.forename: Soojay
authors.initials: S
authors.lastname: Banerjee
authors.forename: Katherine
authors.initials: K
authors.lastname: Gribble
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Kaufman
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wingfield
authors.forename: Robert C
authors.initials: RC
authors.lastname: Griggs
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Ami
authors.initials: A
authors.lastname: Mankodi
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D064211:Connectin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism*; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D064211:Connectin; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; C503771:Myot protein, mouse; D000185:Actinin
keywords: Actin; Actinin; Muscular Dystrophy; Myofibrillar Myopathy; Myotilin; Protein Complex; Protein-Protein Interaction; Skeletal Muscle; Z-disc; ZASP