Structural insight into M-band assembly and mechanics from the titin-obscurin-like-1 complex
Open Access
- 16 February 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (7), 2908-2913
- https://doi.org/10.1073/pnas.0913736107
Abstract
In the sarcomeric M-band, the giant ruler proteins titin and obscurin, its small homologue obscurin-like-1 (obsl1), and the myosin cross-linking protein myomesin form a ternary complex that is crucial for the function of the M-band as a mechanical link. Mutations in the last titin immunoglobulin (Ig) domain M10, which interacts with the N-terminal Ig-domains of obscurin and obsl1, lead to hereditary muscle diseases. The M10 domain is unusual not only in that it is a frequent target of disease-linked mutations, but also in that it is the only currently known muscle Ig-domain that interacts with two ligands—obscurin and obsl1—in different sarcomeric subregions. Using x-ray crystallography, we show the structural basis for titin M10 interaction with obsl1 in a novel antiparallel Ig-Ig architecture and unravel the molecular basis of titin-M10 linked myopathies. The severity of these pathologies correlates with the disruption of the titin-obsl1/obscurin complex. Conserved signature residues at the interface account for differences in affinity that direct the cellular sorting in cardiomyocytes. By engineering the interface signature residues of obsl1 to obscurin, and vice versa, their affinity for titin can be modulated similar to the native proteins. In single-molecule force-spectroscopy experiments, both complexes yield at forces of around 30 pN, much lower than those observed for the mechanically stable Z-disk complex of titin and telethonin, suggesting why even moderate weakening of the obsl1/obscurin-titin links has severe consequences for normal muscle functions.This publication has 36 references indexed in Scilit:
- Muscle Giants: Molecular Scaffolds in SarcomerogenesisPhysiological Reviews, 2009
- The titin-telethonin complex is a directed, superstable molecular bond in the muscle Z-diskProceedings of the National Academy of Sciences of the United States of America, 2009
- Obscurin determines the architecture of the longitudinal sarcoplasmic reticulumJournal of Cell Science, 2009
- Obscurin Interacts with a Novel Isoform of MyBP-C Slow at the Periphery of the Sarcomeric M-Band and Regulates Thick Filament AssemblyMolecular Biology of the Cell, 2009
- The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1American Journal of Human Genetics, 2009
- Cytoplasmic Ig‐domain proteins: Cytoskeletal regulators with a role in human diseaseCell Motility, 2009
- Molecular basis of the C-terminal tail-to-tail assembly of the sarcomeric filament protein myomesinThe EMBO Journal, 2007
- Inference of Macromolecular Assemblies from Crystalline StateJournal of Molecular Biology, 2007
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa crystallographica. Section D, Structural biology, 1997
- The Immunoglobulin Fold: Structural Classification, Sequence Patterns and Common CoreJournal of Molecular Biology, 1994