期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：41
页码：12687-12692
DOI：10.1073/pnas.1512464112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceActin filaments are the fundamental building blocks for cellular motility in muscle cells. However, the regulation of actin filaments in sarcomeres is poorly understood. Lmod is a class of potent tandem-G-actin-binding nucleators in muscle cells. Lmod mutations, deletion, or instability lead to lethal nemaline myopathy. Here we report the crystal structure of actin-Lmod2 complex and complementary functional studies. Our data collectively unraveled the mechanisms of Lmod's essential functions as an actin nucleator and filament length regulator, thus providing a solid foundation for understanding the molecular basis of disease-causing mutations and malfunctions of Lmod that often are life threatening. Most importantly, our results suggest a previously unrecognized level of regulation in mammalian signal transduction mediated by certain tandem-G-actin-binding nucleators. Leiomodin (Lmod) is a class of potent tandem-G-actin-binding nucleators in muscle cells. Lmod mutations, deletion, or instability are linked to lethal nemaline myopathy. However, the lack of high-resolution structures of Lmod nucleators in action severely hampered our understanding of their essential cellular functions. Here we report the crystal structure of the actin-Lmod2162-495 nucleus. The structure contains two actin subunits connected by one Lmod2162-495 molecule in a non-filament-like conformation. Complementary functional studies suggest that the binding of Lmod2 stimulates ATP hydrolysis and accelerates actin nucleation and polymerization. The high level of conservation among Lmod proteins in sequence and functions suggests that the mechanistic insights of human Lmod2 uncovered here may aid in a molecular understanding of other Lmod proteins. Furthermore, our structural and mechanistic studies unraveled a previously unrecognized level of regulation in mammalian signal transduction mediated by certain tandem-G-actin-binding nucleators.
