STRUCTURAL BASIS FOR ACTIVATION OF THE TITIN KINASE DOMAIN DURING MYOFIBRILLOGENESIS

The giant muscle protein titin (connectin) is essential in the tempora l and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. Here we present the crystal s tructure of titin's only catalytic: domain, an autoregulated serine ki nase (titin kinase). The structure shows how the active site is inhibi ted by a tyrosine of the kinase domain. We describe a dual mechanism o f activation of titin kinase that consists of phosphorylation of this tyrosine and binding of calcium/calmodulin to the regulatory tail. The serine kinase domain of titin is the first known non-arginine-asparta te kinase to be activated by phosphorylation. The phosphorylated tyros ine is not located in the activation segment, as in other kinases, but in the P + 1 loop, indicating that this tyrosine is a binding partner of the titin kinase substrate. Titin kinase phosphorylates the muscle protein telethonin in early differentiating myocytes, indicating that this kinase may act in myofibrillogenesis.