title: M line-deficient titin causes cardiac lethality through impaired maturation of the sarcomere.
abstract: Titin, the largest protein known to date, has been linked to sarcomere assembly and function through its elastic adaptor and signaling domains. Titin's M-line region contains a unique kinase domain that has been proposed to regulate sarcomere assembly via its substrate titin cap (T-cap). In this study, we use a titin M line-deficient mouse to show that the initial assembly of the sarcomere does not depend on titin's M-line region or the phosphorylation of T-cap by the titin kinase. Rather, titin's M-line region is required to form a continuous titin filament and to provide mechanical stability of the embryonic sarcomere. Even without titin integrating into the M band, sarcomeres show proper spacing and alignment of Z discs and M bands but fail to grow laterally and ultimately disassemble. The comparison of disassembly in the developing and mature knockout sarcomere suggests diverse functions for titin's M line in embryonic development and the adult heart that not only involve the differential expression of titin isoforms but also of titin-binding proteins.
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin-Buch, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weinert
authors.forename: Nora
authors.initials: N
authors.lastname: Bergmann
authors.forename: Xiuju
authors.initials: X
authors.lastname: Luo
authors.forename: Bettina
authors.initials: B
authors.lastname: Erdmann
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
mesh_terms: D000818:Animals; D064211:Connectin; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics*; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012518:Sarcomeres / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D064211:Connectin; D009124:Muscle Proteins; D011494:Protein Kinases