Paul Matsudaira
Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142
Actin crosslinking proteins organize actin filaments into networks and bundles of filaments. A distinctive hallmark of crosslinking proteins is their modular organization, actin binding domains are functional modules shared among different actin binding proteins, the binding sites are spaced apart by spacer modules composed of repeated motifs coiled coils, triple helices, beta-sheets, and assorted globular domains. For example, most crosslinking proteins including fimbrin, alpha-actinin, spectrin, filamin, BPAG1, and dystrophin belong to a large superfamily which share a common calponin-homology domain. However, other crosslinking proteins such as villin and scruin belong to unrelated superfamilies (cofilin and beta-propeller superfamilies) of proteins. I will review recent biochemical and collaborative structural (X-ray diffraction, NMR, and cryoEM) studies on the actin binding domains of villin, fimbrin, and scruin, describe their binding sites on actin, and discuss biochemical evidence identifying binding sites on the crosslinking proteins. Our studies on the actin bundle in intestinal microvilli and the Limulus sperm acrosome reveal that villin, fimbrin, and scruin bind different regions on actin and employ different mechanisms for building an actin bundle.