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M line-deficient titin causes cardiac lethality through impaired maturation of the sarcomere

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Official URL:https://doi.org/10.1083/jcb.200601014
PubMed:View item in PubMed
Creators Name:Weinert, S. and Bergmann, N. and Luo, X. and Erdmann, B. and Gotthardt, M.
Journal Title:Journal of Cell Biology
Journal Abbreviation:J Cell Biol
Volume:173
Number:4
Page Range:559-570
Date:22 May 2006
Keywords:Developmental Gene Expression Regulation, Lethal Genes, Heart, Congenital Heart Defects, Knockout Mice, Transmission Electron Microscopy, Muscle Proteins, Mutation, Myocardium, Cardiac Myocytes, Phosphorylation, Protein Binding, Protein Kinases, Tertiary Protein Structure, Sarcomeres, Animals, Mice
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.
ISSN:0021-9525
Publisher:Rockefeller University Press (U.S.A.)
Additional Information:Copyright (c) 2006 by The Rockefeller University Press
Item Type:Article

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