Capping actin filament growth: tropomodulin in muscle and nonmuscle cells.

Abstract

Actin filament lengths are precisely regulated and very stable in the sarcomeres of striated muscle, in the erythrocyte membrane skeleton, and in cell protrusions such as microvilli in intestinal epithelial cells and stereocilia in hair cells of the inner ear. In contrast, in motile cells, actin filament lengths are dynamically regulated when cells extend lamellipodia. Control of actin filament lengths and dynamics in cells is expected to be achieved in part by capping proteins that prevent filament growth or shrinkage by blocking subunit exchange at both the fast growing (barbed) and slow growing (pointed) filament ends. Much is known about how barbed end capping proteins control actin filament assembly and length in many cells, but little is known about the significance of regulating actin filament assembly at the pointed end. Tropomodulin is the only known capping protein for the pointed ends of actin filaments and is a approximately 40-kD protein that is expressed in erythrocytes, striated muscle, lens fiber cells, some regions of the adult brain, as well as sensory neurons and epithelial cells of the inner ear. A related isoform (59% identical at the protein level) is expressed principally in neurons of both embryonic and adult brain. In striated muscle and in erythrocytes, tropomodulin is tightly associated with the actin filament pointed ends where it functions to maintain actin filament length in vivo (for recent reviews, see Fowler, 1996; Gregorio and Fowler, 1996). Unlike proteins that cap actin filament barbed ends, tropomodulin also binds tropomyosin and requires tropomyosin for tight capping of actin filament pointed ends. Mapping of functional domains on tropomodulin shows that the COOH-terminal end of tropomodulin is important for actin filament pointed end capping activity while the NH2-terminal portion of tropomodulin contains the tropomyosin binding domain. Searches of protein and EST databases for tropomodulin-like sequences reveal a number of proteins with homologies to both the tropomyosin binding and the actin filament capping portions of tropomodulin. In particular, we have identified a tropomodulin-like 64-kD protein that is principally expressed in smooth muscle cells. We anticipate that tropomodulin and this 64-kD protein are members of a larger family of tropomyosin and actin binding proteins that are responsible for capping actin filament pointed ends and regulating actin filament lengths in muscle and nonmuscle cells.