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Labs visualize cell “skeleton” structure

The protein filamin and its close relatives help assemble filaments of the protein actin into a kind of cellular skeleton. A number of genetic diseases result from defects in this cytoskeleton. Researchers led by Charles V. Sindelar, PhD, associate professor of molecular biophysics and biochemistry, and David A. Calderwood, PhD, associate professor of pharmacology and of cell biology, have used cryo-EM to visualize the 3D structure of filamin’s actin-binding section as it attaches to actin.

The protein, they found, has three actin binding sites. Each has slight nuances in how it binds to actin and which part of the actin structure it interacts with. They then showed how slight changes in filamin’s actin-binding section, or domain, can interrupt its connection to actin.

The findings, published Sept. 16 in Nature Structural Molecular Biology, explain why mutations linked to genetic diseases are so detrimental. The actin-binding domain must open and close to bind actin, and some disease mutations apparently enhance this opening, leading to increasing binding, while others more directly disrupt the interactions between one of filamin’s actin-binding sites and actin, leading to an entirely separate disease.