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Disease-Associated Mutant α-Actinin-4 Reveals a Mechanism for Regulating Its F-Actin-Binding Affinity
Astrid Weins, Johannes S. Schlondorff, Fumihiko Nakamura, Bradley M. Denker, John H. Hartwig, Thomas P. Stossel and Martin R. Pollak
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 41 (Oct. 9, 2007), pp. 16080-16085
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25449272
Page Count: 6
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α-Actinin-4 is a widely expressed protein that employs an actin-binding site with two calponin homology domains to crosslink actin filaments (F-actin) in a Ca²⁺-sensitive manner in vitro. An inherited, late-onset form of kidney failure is caused by point mutations in the α-actinin-4 actin-binding domain. Here we show that α-actinin-4/F-actin aggregates, observed in vivo in podocytes of humans and mice with disease, likely form as a direct result of the increased actin-binding affinity of the protein. We document that exposure of a buried actin-binding site 1 in mutant α-actinin-4 causes an increase in its actin-binding affinity, abolishes its Ca²⁺ regulation in vitro, and diverts its normal localization from actin stress fibers and focal adhesions in vivo. Inactivation of this buried actin-binding site returns the affinity of the mutant to that of the WT protein and abolishes aggregate formation in cells. In vitro, actin filaments crosslinked by the mutant α-actinin-4 exhibit profound changes of structural and biomechanical properties compared with WT α-actinin-4. On a molecular level, our findings elucidate the physiological importance of a dynamic interaction of α-actinin with F-actin in podocytes in vivo. We propose that a conformational change with full exposure of actin-binding site 1 could function as a switch mechanism to regulate the actin-binding affinity of α-actinin and possibly other calponin homology domain proteins under physiological conditions.
Proceedings of the National Academy of Sciences of the United States of America © 2007 National Academy of Sciences