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Publication Abstract from PubMed

M10 is the most C-terminal immunoglobulin (Ig) domain of the giant protein titin and a frequent target of disease-linked mutations. Currently, it is the only known muscle Ig-domain able to interact with two alternative ligands - obscurin and obscurin-like-1 (Obsl1) - in different sarcomeric subregions. Obscurin and Obsl1 use their homologous N-terminal Ig domain (O1 in obscurin and OL1 in Obsl1) to bind M10 in a mutually exclusive manner. We present here the X-ray structure of the human titin:obscurin M10:O1 complex extending our previous work on the M10:OL1 interaction. Similar to M10:OL1, the M10:O1 complex displays a chevron-shaped antiparallel Ig-Ig architecture held together by a conserved molecular interface, which we validated by isothermal titration calorimetry and sorting experiments in neonatal rat cardiomyocytes (NRCs). O1 although structurally related to OL1 and M10, both members of the I-set Ig family, presents an intriguing switch of its betaA' strand. This leads to structural differences between the complexes, particularly, for the 'open-side' of the chevron-shaped assembly. A bioinformatics analysis reveals that the betaA'-switch observed for O1 is rare and that it is involved in mediating protein-protein interactions. Molecular Dynamics simulations also suggest that this topological alteration substantially increases local flexibility compared to the conventional I-set Ig domains. The O1/OL1 Ig domains are candidate discriminatory structural modules potentially directing the binding of specific additional partners at the M-band. Cellular sorting experiments in NRCs are consistent with the view that the titin:obscurin/Obsl1 complexes might be a platform for higher order interactions.

The Crystal Structure of the Human Titin:Obscurin Complex Reveals a Conserved Yet Specific Muscle M-band Zipper Module.,Pernigo S, Fukuzawa A, Pandini A, Holt M, Kleinjung J, Gautel M, Steiner RA J Mol Biol. 2014 Dec 6. pii: S0022-2836(14)00615-9. doi:, 10.1016/j.jmb.2014.11.019. PMID:25490259^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.