Abstract
How proteins sharing a common fold have evolved different functions is a fundamental question in biology. Tropomodulins (Tmods) are prototypical actin filament pointed-end-capping proteins, whereas their homologues, Leiomodins (Lmods), are powerful filament nucleators. We show that Tmods and Lmods do not compete biochemically, and display similar but distinct localization in sarcomeres. Changes along the polypeptide chains of Tmods and Lmods exquisitely adapt their functions for capping versus nucleation. Tmods have alternating tropomyosin (TM)- and actin-binding sites (TMBS1, ABS1, TMBS2 and ABS2). Lmods additionally contain a C-terminal extension featuring an actin-binding WH2 domain. Unexpectedly, the different activities of Tmods and Lmods do not arise from the Lmod-specific extension. Instead, nucleation by Lmods depends on two major adaptations—the loss of pointed-end-capping elements present in Tmods and the specialization of the highly conserved ABS2 for recruitment of two or more actin subunits. The WH2 domain plays only an auxiliary role in nucleation.
Highlights
How proteins sharing a common fold have evolved different functions is a fundamental question in biology
We recently showed that ABS1 binds on top of the first actin subunit at the pointed end of the actin filament, adopting an extended but ordered structure, whereas ABS2 binds at the interface between the first three subunits of the filament, interacting mostly with the second subunit[7]
The unique characteristics of the C-terminal extension suggested that Lmods could function as actin filament nucleators, which we initially demonstrated for Lmod[2], and was recently shown for Lmod[3]
Summary
How proteins sharing a common fold have evolved different functions is a fundamental question in biology. Tropomodulins (Tmods) constitute a conserved family of four isoforms that work in conjunction with one of several tropomyosin (TM) isoforms to cap the pointed end of actin filaments in cytoskeletal structures characterized by their uniform distribution of the lengths of actin filaments[1] These structures include the sarcomere of cardiac and skeletal muscle cells and the spectrin-based membrane skeleton[1,2]. We show that ABS2, and not the C-terminal extension, is the main factor distinguishing Lmods and Tmods as filament nucleators and pointed-end-capping proteins, respectively. This was a surprising finding since ABS2 is the most highly conserved region among these proteins. We found that the WH2 domaincontaining extension of Lmods plays only an auxiliary role in nucleation
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