title: A class III PDZ binding motif in the myotilin and FATZ families binds enigma family proteins: a common link for Z-disc myopathies.
abstract: Interactions between Z-disc proteins regulate muscle functions and disruption of these interactions results in muscle disorders. Mutations in Z-disc components myotilin, ZASP/Cypher, and FATZ-2 (calsarcin-1/myozenin-2) are associated with myopathies. We report here that the myotilin and the FATZ (calsarcin/myozenin) families share high homology at their final C-terminal five amino acids. This C-terminal E[ST][DE][DE]L motif is present almost exclusively in these families and is evolutionary conserved. We show by in vitro and in vivo studies that proteins from the myotilin and FATZ (calsarcin/myozenin) families interact via this novel type of class III PDZ binding motif with the PDZ domains of ZASP/Cypher and other Enigma family members: ALP, CLP-36, and RIL. We show that the interactions can be modulated by phosphorylation. Calmodulin-dependent kinase II phosphorylates the C terminus of FATZ-3 (calsarcin-3/myozenin-3) and myotilin, whereas PKA phosphorylates that of FATZ-1 (calsarcin-2/myozenin-1) and FATZ-2 (calsarcin-1/myozenin-1). This is the first report of a binding motif common to both the myotilin and the FATZ (calsarcin/myozenin) families that is specific for interactions with Enigma family members.
authors.affiliation: Department of Pathology and Neuroscience Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Pernilla
authors.initials: P
authors.lastname: von Nandelstadh
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ismail
authors.forename: Chiara
authors.initials: C
authors.lastname: Gardin
authors.forename: Heli
authors.initials: H
authors.lastname: Suila
authors.forename: Ivano
authors.initials: I
authors.lastname: Zara
authors.forename: Anna
authors.initials: A
authors.lastname: Belgrano
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valle
authors.forename: Olli
authors.initials: O
authors.lastname: Carpen
authors.forename: Georgine
authors.initials: G
authors.lastname: Faulkner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002522:Chlorocebus aethiops; D064211:Connectin; D017124:Conserved Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008024:Ligands; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism*; D009135:Muscular Diseases / Q000378:metabolism*; D009928:Organ Specificity; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D064211:Connectin; D003598:Cytoskeletal Proteins; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D008024:Ligands; C577290:MYOT protein, human; C419780:MYOZ1 protein, human; C455624:MYOZ3 protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010455:Peptides; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2