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Mechanism of actin filament pointed-end capping by tropomodulin

Science  25 Jul 2014:
Vol. 345, Issue 6195, pp. 463-467
DOI: 10.1126/science.1256159

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Making tropomodulin find the right point

Actin filaments are a key component of the cell's cytoskeleton. Actin filaments have a characteristic polarized architecture with a so-called barbed end and a pointed end—so described because of how the filaments look under the electron microscope when they are coated with tropomyosin. Rao et al. describe crystal structures of a protein that uniquely binds and caps the pointed end of actin filaments. This protein, tropomodulin, binds to several actin subunits and to a couple of tropomyosin molecules, which generates a high-affinity specific cap to the filaments by combining low-affinity interactions.

Science, this issue p. 463

Abstract

Proteins that cap the ends of the actin filament are essential regulators of cytoskeleton dynamics. Whereas several proteins cap the rapidly growing barbed end, tropomodulin (Tmod) is the only protein known to cap the slowly growing pointed end. The lack of structural information severely limits our understanding of Tmod’s capping mechanism. We describe crystal structures of actin complexes with the unstructured amino-terminal and the leucine-rich repeat carboxy-terminal domains of Tmod. The structures and biochemical analysis of structure-inspired mutants showed that one Tmod molecule interacts with three actin subunits at the pointed end, while also contacting two tropomyosin molecules on each side of the filament. We found that Tmod achieves high-affinity binding through several discrete low-affinity interactions, which suggests a mechanism for controlled subunit exchange at the pointed end.

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