Dynactin is a multisubunit protein complex that works in conjunction with the microtubule-based motor, cytoplasmic dynein, to support a range of subcellular motile functions. Dynactin enhances motor processivity and serves as an adaptor protein that allows dynein to bind membrane and protein cargoes. Dynactin can also function independently of dynein, to tether protein complexes and regulatory molecules to microtubules. Dynactin has even been shown to interact with motors other than dynein. To perform these diverse functions, dynactin relies on multiple binding activities that are distributed across its structure. Motor binding uses one part of the molecule, microtubule binding and processivity enhancement another, and cargo binding yet another. Dynactin's structural integrity is maintained by its dynamitin (p50) subunit, which forms a flexible bridge that anchors the motor and microtubule-binding subunit to the cargo-binding domain.
Specific Aim 1 is focused on understanding dynamitin's interactions with other dynactin subunits and with itself.
Specific Aim 2 describes experiments to clearly define the molecular and ultrastructural basis of the dynein/dynactin interaction. The nucleus is one of many organelles that interacts with dynactin and dynein. Motor activity can power nuclear translocation and also the nuclear envelope rupture that occurs at the onset of mitosis. Work from our lab suggests that dynactin binds nuclei using subunits that are located at the very end of the cargo-binding domain. The goal of Specific Aim 3 is to elucidate the mechanism of cell cycle regulation and identify components of the nuclear envelope that bind dynactin. We recently discovered that dynactin is required for the normal metabolism and microtubule-dependent cytoplasmic tethering of signal transduction molecules. The link to dynactin is a pair of subunits, p25 and p27, that are loosely associated with the dynactin """"""""core"""""""" structure, p25 and p27 may be exchangeable subunits that allow different cytosolic components to be targeted to dynactin and microtubules. The dynamic interactions between p25/p27, the dynactin core and microtubules are evaluated in experiments described in Specific Aim 4.
| Cavolo, Samantha L; Zhou, Chaoming; Ketcham, Stephanie A et al. (2015) Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles. Mol Biol Cell 26:2664-72 |
| Day, Charles A; Baetz, Nicholas W; Copeland, Courtney A et al. (2015) Microtubule motors power plasma membrane tubulation in clathrin-independent endocytosis. Traffic 16:572-90 |
| Chowdhury, Saikat; Ketcham, Stephanie A; Schroer, Trina A et al. (2015) Structural organization of the dynein-dynactin complex bound to microtubules. Nat Struct Mol Biol 22:345-7 |
| Imai, Hiroshi; Narita, Akihiro; Maéda, Yuichiro et al. (2014) Dynactin 3D structure: implications for assembly and dynein binding. J Mol Biol 426:3262-3271 |
| Cheong, Frances Ka Yan; Feng, Lijuan; Sarkeshik, Ali et al. (2014) Dynactin integrity depends upon direct binding of dynamitin to Arp1. Mol Biol Cell 25:2171-80 |
| Yeh, Ting-Yu; Kowalska, Anna K; Scipioni, Brett R et al. (2013) Dynactin helps target Polo-like kinase 1 to kinetochores via its left-handed beta-helical p27 subunit. EMBO J 32:1023-35 |
| DeBerg, Hannah A; Blehm, Benjamin H; Sheung, Janet et al. (2013) Motor domain phosphorylation modulates kinesin-1 transport. J Biol Chem 288:32612-21 |
| Wang, Shusheng; Ketcham, Stephanie A; Schön, Arne et al. (2013) Nudel/NudE and Lis1 promote dynein and dynactin interaction in the context of spindle morphogenesis. Mol Biol Cell 24:3522-33 |
| Blehm, Benjamin H; Schroer, Trina A; Trybus, Kathleen M et al. (2013) In vivo optical trapping indicates kinesin's stall force is reduced by dynein during intracellular transport. Proc Natl Acad Sci U S A 110:3381-6 |
| Yeh, Ting-Yu; Quintyne, Nicholas J; Scipioni, Brett R et al. (2012) Dynactin's pointed-end complex is a cargo-targeting module. Mol Biol Cell 23:3827-37 |
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