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Lecture 13

Lecture 13: "Actin Filaments - Microfilaments II"

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Biology 2382B
Robert Cumming

Cell Biology Lecture No. 13: Actin Filaments – Microfilaments II th Wednesday February 27 , 2013 Actin Polymerization & Critical Concentration: -ATP-bound actin subunits add faster at the plus-end than at the minus-end of an actin filament, resulting in a lower critical concentration and treadmilling at steady state. The rate of addition of ATP-G- actin is much faster at the plus-end than at the minus-end, whereas the rate of dissociation of ADP-G- actin is similar at the two ends. This difference results in a lower critical concentration at the plus-end (0.12μM). At steady state, ATP-actin is added preferentially at the plus-end, giving rise to a short region of the filament containing ATP-actin and regions containing ADP-P-actiniand ADP-actin toward the minus-end. At steady state, ATP-G-actin subunits add preferentially to the plus-end, while ADP-G-actin subunits disassemble from the minus-end, giving rise to a treadmilling of subunits. The critical concentration of the minus-end of actin is 0.60μM. Treadmilling can also be achieved in tubulin/microtubules, but most often the minus-end is capped and removal cannot occur. The Regulation Of Actin Polymerization & Anti-Capping Proteins: -Actin-binding proteins regulate the rate of assembly and disassembly as well as the availability of G- actin for polymerization. In the profilin (promotes actin polymerization) cycle, profilin binds ADP-G-actin and catalyzes the exchange of ADP for ATP. The ATP-G-actin-profilin complex can deliver actin to the plus- end of a filament with dissociation and recycling of profilin. ln the cofilin (enhances depolymerization) cycle, cofilin binds preferentially to filaments containing ADP-actin, inducing them to fragment and thus enhancing depolymerization by making more filament ends. In the thymosin (sequesters actin) cycle, G-actin available from the actin-profilin equilibrium is bound by thymosin, sequestering it from polymerization. As the free G-actin concentration is lowered by polymerization, G- actin-thymosin dissociates to make free G-actin available for association with profilin and further polymerization. Most of the free G-actin in the cell is bound by thymosin. - Capping proteins block assembly and disassembly at microfilament ends. CapZ is a capping protein that blocks the plus-end, which is where microfilaments normally grow, so its function is to limit actin dynamics to the minus-end (prevent assembly). The capping protein tropornodulin blocks minus-ends, where microfilament disassembly normally occurs, thus the major function of tropomodulin is to stabilize filaments (prevent disassembly). Certain actin-disrupting drugs include cytochalasin (which depolymerizes actin filaments) and phalloidin (which stabilizes actin filaments; prevents disassembly). Actin Assembly: -Formins have a domain called FH2 that can form a dimer and nucleate filament assembly. The dimer binds two actin subunits and, by rocking back and forth, can allow the insertion of additional subunits between the FH2 domain and the plus-end of the growing filament. The FH2 domain protects the plus- end from being capped by capping proteins. The inactive formin is activated by binding its Rho-binding domain (RBD) to membrane-bound active Rho-GTPase, resulting in exposure of the formin's FH2 domain, which can then nucleate the assembly of a new filament. All formins have an FHl domain adjacent to the FH2 domain. The proline-rich FHl domain is a site for recruitment of profilin-ATP-G-actin complexes that can then be "fed" into the growing plus-end. Actin Branching: -To nucleate actin assembly efficiently, the activating part of a Nucleation Promoting Factor (NPF) is shown with its W (WH2), C (connector), and A (acidic) domains. An actin subunit binds to the W domain and then the A domain binds the Arp2/3 complex. This interaction induces a conformational change in the Arp2/3 complex, and after binding to the side of an actin filament, the actin subunit bound to the W domain binds to the Arp2/3 complex, which then initiates the assembly of an actin filament at the available plus-end. -WASp is inactive due to an intramolecular interaction that masks the WCA domain. On binding the membrane-bound active small G protein Cdc42-GTPase (a member of the Rho family) through its Rho- binding domain (RBD), the intramolecular interaction in WASp is relieved, exposing the W domain to bind actin and the acidic A domain for activation of t
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