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

Vertebrate-striated muscle is assumed to owe its remarkable order to the mo lecular 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 ide ntification of a third giant protein from vertebrate muscle, obscurin, enco ded on chromosome 1q42. Obscurin is similar to 800 kD and is expressed spec ifically in skeletal and cardiac muscle. The complete cDNA sequence of obsc urin reveals a modular architecture, consisting of >67 intracellular immuno globulin (Ig)- or fibronectin-3-like domains with multiple splice variants. A large region of obscurin shows a modular architecture of tandem Ig domai ns 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, an d a Rho guanine nucleotide exchange factor domain in the COOH-terminal regi on suggest that obscurin is involved in Ca2+/calmodulin, as well as G prote in-coupled signal transduction in the sarcomere.