2WP3

Crystal structure of the Titin M10-Obscurin like 1 Ig complex

Summary for 2WP3

• Entry DOI: 10.2210/pdb2wp3/pdb
• Related: 1BPV 1G1C 1NCT 1NCU 1TIT 1TIU 1TKI 1TNM 1TNN 1WAA 1YA5 2A38 2BK8 2CPC 2F8V 2J8H 2J8O 2WWK 2WWM
• Descriptor: OBSCURIN-LIKE PROTEIN 1, TITIN, GLYCEROL, ... (5 entities in total)
• Functional Keywords: transferase-structural protein complex, sarcomere, immunoglobulin domain, limb-girdle muscular dystrophy, serine/threonine-protein kinase, atp-binding, kelch repeat, cardiomyopathy, calmodulin-binding, transferase/structural protein
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm (Probable): Q8WZ42
• Total number of polymer chains: 2
• Total formula weight: 22571.29

Authors

Pernigo, S.,Fuzukawa, A.,Gautel, M.,Steiner, R.A. (deposition date: 2009-08-02, release date: 2010-02-16, Last modification date: 2024-10-23)

Primary citation

Pernigo, S.,Fukuzawa, A.,Bertz, M.,Holt, M.,Rief, M.,Steiner, R.A.,Gautel, M.
Structural Insight Into M-Band Assembly and Mechanics from the Titin-Obscurin-Like-1 Complex.
Proc.Natl.Acad.Sci.USA, 107:2908-, 2010

PubMed 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.

PubMed: 20133654
DOI: 10.1073/PNAS.0913736107

Experimental method

X-RAY DIFFRACTION (1.48 Å)