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PDBsum entry 2wp3
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Transferase/structural protein
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PDB id
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2wp3
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References listed in PDB file
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Key reference
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Title
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Structural insight into m-Band assembly and mechanics from the titin-Obscurin-Like-1 complex.
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Authors
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S.Pernigo,
A.Fukuzawa,
M.Bertz,
M.Holt,
M.Rief,
R.A.Steiner,
M.Gautel.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
2908-2913.
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PubMed id
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Abstract
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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.
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