The long-term goal of this program project is to understand the molecular mechanisms that allow Arp2/3 complex to control actin filament assembly during endocytosis and cellular motility. The mechanism of action of Arp2/3 complex is so complicated that a team effort is required. Our group of four geographically dispersed laboratories combines x-ray crystallography, electron microscopy, image processing and molecular biology to address technically challenging questions. Structural insights from his ongoing collaboration will provide important clues about reaction mechanisms and also help to design experiments to measure kinetic and thermodynamic constants and to study actin assembly in live cells. Project 1 (Pollard) proposes a combination of biochemical and x-ray crystallographic experiments to obtain detailed structural information regarding conformational changes and macromolecular interactions of Arp2/3 complex. Project 2 (Li) proposes a combination of biophysical studies on interaction's of nucleation promoting factors with purified Arp2/3 complex and microscopic analysis of mouse cells lacking subunits of Arp2/3 complex. Project 3 (Hanein) proposes electron microscopy of purified Arp2/3 complex, actin filament branches and of actin networks in mouse cells with and without functional Arp2/3 complex. Project 4 (Volkmann) proposes computational methods to extract the maximal amount of information from spectroscopy experiments in projects 1 and 2 and the electron micrographs from project 3.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-CB-D (40))
Program Officer
Gindhart, Joseph G
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Anderson, Karen L; Page, Christopher; Swift, Mark F et al. (2017) Nano-scale actin-network characterization of fibroblast cells lacking functional Arp2/3 complex. J Struct Biol 197:312-321
Wang, Pei-Shan; Chou, Fu-Sheng; Ramachandran, Sreekumar et al. (2016) Crucial roles of the Arp2/3 complex during mammalian corticogenesis. Development 143:2741-52
Pollard, Thomas D (2016) Actin and Actin-Binding Proteins. Cold Spring Harb Perspect Biol 8:
Page, Christopher; Hanein, Dorit; Volkmann, Niels (2015) Accurate membrane tracing in three-dimensional reconstructions from electron cryotomography data. Ultramicroscopy 155:20-26
Jurgenson, Christopher T; Pollard, Thomas D (2015) Crystals of the Arp2/3 complex in two new space groups with structural information about actin-related protein 2 and potential WASP binding sites. Acta Crystallogr F Struct Biol Commun 71:1161-8
Li, Yongchao; Wang, Pei-Shan; Lucas, George et al. (2015) ARP2/3 complex is required for directional migration of neural stem cell-derived oligodendrocyte precursors in electric fields. Stem Cell Res Ther 6:41
Tee, Yee Han; Shemesh, Tom; Thiagarajan, Visalatchi et al. (2015) Cellular chirality arising from the self-organization of the actin cytoskeleton. Nat Cell Biol 17:445-57
Suraneni, Praveen; Fogelson, Ben; Rubinstein, Boris et al. (2015) A mechanism of leading-edge protrusion in the absence of Arp2/3 complex. Mol Biol Cell 26:901-12
Volkmann, Niels; Page, Christopher; Li, Rong et al. (2014) Three-dimensional reconstructions of actin filaments capped by Arp2/3 complex. Eur J Cell Biol 93:179-83
Volkmann, Niels (2014) The joys and perils of flexible fitting. Adv Exp Med Biol 805:137-55

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