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Published 9 July 2001. doi:10.1083/jcb.200102110
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© The Rockefeller University Press, 0021-9525/2001/7/123 $5.00
The Journal of Cell Biology, Volume 154, Number 1, July 9, 2001 123-136


Article

Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly



Paul Young1, Elisabeth Ehler2 and Mathias Gautel3

1 European Molecular Biology Laboratory, Structural Biology Division, 69117 Heidelberg, Germany
2 Institute of Cell Biology, Hönggerberg, CH-8093 Zürich, Switzerland
3 Department of Physical Biochemistry, Max-Planck Institute for Molecular Physiology, 44202 Dortmund, Germany

Address correspondence to Dr. Mathias Gautel, Max-Planck Institute for Molecular Physiology, Department of Physical Biochemistry, Postfach 500 247, 44202 Dortmund, Germany. Tel.: (49) 231-133-2354. Fax: (49) 231-133-2399. E-mail: mathias.gautel{at}mpi-dortmund.mpg.de

Vertebrate-striated muscle is assumed to owe its remarkable order to the molecular ruler functions of the giant modular signaling proteins, titin and nebulin. It was believed that these two proteins represented unique results of protein evolution in vertebrate muscle. In this paper we report the identification of a third giant protein from vertebrate muscle, obscurin, encoded on chromosome 1q42. Obscurin is ~800 kD and is expressed specifically in skeletal and cardiac muscle. The complete cDNA sequence of obscurin reveals a modular architecture, consisting of >67 intracellular immunoglobulin (Ig)- or fibronectin-3–like domains with multiple splice variants. A large region of obscurin shows a modular architecture of tandem Ig domains reminiscent of the elastic region of titin. The COOH-terminal region of obscurin interacts via two specific Ig-like domains with the NH2-terminal Z-disk region of titin. Both proteins coassemble during myofibrillogenesis. During the progression of myofibrillogenesis, all obscurin epitopes become detectable at the M band. The presence of a calmodulin-binding IQ motif, and a Rho guanine nucleotide exchange factor domain in the COOH-terminal region suggest that obscurin is involved in Ca2+/calmodulin, as well as G protein–coupled signal transduction in the sarcomere.

Key Words: obscurin; Rho GTPases; GEF proteins; myofibril; heart muscle


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