Cell motility and force generation are fundamental features of living organisms. Actin, one of the most conserved and aboundant proteins in eukaryotic cells, plays a key role in these processes. The long-term goal of this research is to provide detailed understanding of structure and dynamic events that underlie force generation by actomyosin and the remodeling of actin filaments for cellular needs. This goal will be pursued through a combination of x-ray structure determination of actin oligomers and their complexes, and solution studies probing actin filaments structure, dynamics, interactions, and fuction via cross-linking, kinetic, spectroscopic, electron microscopy, and mutagenesis methods.
The specific aims of the three projects of this study are: I, (i-iv) To map by radiolysis, mass spectrometry, cleavage, and cross-linking methods the interaction sites of actin and cofilin, and actin and myosin in strongly and weakly bound complexes. II. (i-iii) To crystallize and solve the structures of actin dimers, tetramers, and their complexes with cofilin, gelsolin fragments, capping proteins, and myosin heads (S1). . (i-iii) To stabilize the early forms of actin filaments and assess the role of anti-parallel dimers in the growth of filament branches;(iy) To test by spectroscopic and mutagenesis methods the structure of the DNase I binding loop on actin;(v) To determine the mechanism of actin filament severing by cofilin and gelsolin, and to clarify the activation of cofilin function by the actin interacting protein Aip1. Detailed understanding of the structure, dynamics and interactions of actin should clarify the mechanism of its function in muscle contraction and in cellular processes, such as wound healing, cancer metastasis, chemotaxis of immune cells and host-pathogen interactions. Ultimately, this understanding should help in the development of therapeutic interventions as drugs that influence actin interactions are discovered.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function C Study Section (MSFC)
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Gindhart, Joseph G
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Grintsevich, Elena E (2017) Remodeling of Actin Filaments by Drebrin A and Its Implications. Adv Exp Med Biol 1006:61-82
Grintsevich, Elena E; Ge, Peng; Sawaya, Michael R et al. (2017) Catastrophic disassembly of actin filaments via Mical-mediated oxidation. Nat Commun 8:2183
Grintsevich, Elena E; Yesilyurt, Hunkar Gizem; Rich, Shannon K et al. (2016) F-actin dismantling through a redox-driven synergy between Mical and cofilin. Nat Cell Biol 18:876-85
Mikati, Mouna A; Breitsprecher, Dennis; Jansen, Silvia et al. (2015) Coronin Enhances Actin Filament Severing by Recruiting Cofilin to Filament Sides and Altering F-Actin Conformation. J Mol Biol 427:3137-47
Oztug Durer, Zeynep A; McGillivary, Rebecca M; Kang, Hyeran et al. (2015) Metavinculin Tunes the Flexibility and the Architecture of Vinculin-Induced Bundles of Actin Filaments. J Mol Biol 427:2782-98
Ge, Peng; Durer, Zeynep A Oztug; Kudryashov, Dmitri et al. (2014) Cryo-EM reveals different coronin binding modes for ADP- and ADP-BeFx actin filaments. Nat Struct Mol Biol 21:1075-81
Gurel, Pinar S; Ge, Peng; Grintsevich, Elena E et al. (2014) INF2-mediated severing through actin filament encirclement and disruption. Curr Biol 24:156-64
Grintsevich, Elena E; Reisler, Emil (2014) Drebrin inhibits cofilin-induced severing of F-actin. Cytoskeleton (Hoboken) 71:472-83
Sharma, Shivani; Grintsevich, Elena E; Woo, JungReem et al. (2014) Nanostructured self-assembly of inverted formin 2 (INF2) and F-actin-INF2 complexes revealed by atomic force microscopy. Langmuir 30:7533-9
Mikati, Mouna A; Grintsevich, Elena E; Reisler, Emil (2013) Drebrin-induced stabilization of actin filaments. J Biol Chem 288:19926-38

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