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

M line–deficient titin causes cardiac lethality through impaired maturation of the sarcomere 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. Footnotes Abbreviations used in this paper: FHL2, four and a half LIM-only protein 2; MEx, M-line exon; MuRF, muscle-specific RING finger protein; Nbr1, neighbor of BRCA1 gene 1; Sqstm1, sequestosome 1; T-cap, titin cap. Submitted: 4 January 2006 Accepted: 18 April 2006 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

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

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Publisher
Rockefeller University Press
Copyright
© 2006 Rockefeller University Press
ISSN
0021-9525
eISSN
1540-8140
DOI
10.1083/jcb.200601014
pmid
16702235
Publisher site
See Article on Publisher Site

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. Footnotes Abbreviations used in this paper: FHL2, four and a half LIM-only protein 2; MEx, M-line exon; MuRF, muscle-specific RING finger protein; Nbr1, neighbor of BRCA1 gene 1; Sqstm1, sequestosome 1; T-cap, titin cap. Submitted: 4 January 2006 Accepted: 18 April 2006

Journal

The Journal of Cell Biology – Rockefeller University Press

Published: May 22, 2006

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