Microtubules modeling

Fig. 9 Insight of the outer (a) and (b) inner surface of a high resolution microtubule model, showing two different types of pores, I and II (see text). Green beads, polar residues yellow beads, hydrophobic residues red beads, acid residues blue beads, basic residues white beads, paclitaxel bound at its site grey beads, nucleotide. Detail of a pore type I viewed from above (c). Ribbon representation of two neighbour P-tubulin subunits as seen from the plus end of the microtubule, paclitaxel, GDP and the four residues forming a putative taxoid binding site are shown in Van der Waals representation. Taken from [22]...

Keywords Diffraction, Dynamics, Electron crystallography, Epothilone, Lauli-malide, Microtubules, Modeling, Paclitaxel, SAR, Taxol, Tubulin... 

FIGURE 17.3 A model of the GTP-depeu-deut treadmiUing process. Both a- aud /J-tubuliu possess two different binding sites for GTP. The polymerization of tubuliu to form microtubules is driven by GTP hydrolysis in a process that is only beginning to be understood in detail. 

Docetaxel, another taxane, binds to tubulin to promote microtubule assembly. The pharmacokinetics of docetaxel are best described by a three-compartment model, with an a half-life of 0.08 hours, a 3 half-life of 1.6 to 1.8 hours, and a terminal half-life of 65 to 73 hours.14 Docetaxel has activity in the treatment of breast, non-small cell lung, prostate, bladder, esophageal, stomach, ovary, and head and neck cancers. Dexamethasone, 8 mg twice daily for 3 days starting the day before treatment, is used to prevent the fluid retention syndrome associated with docetaxel and possible hypersensitivity reactions. The fluid... 

Goncgy One of the popular models to explain the 90° rotation of centrosomes in PI invokes capture of astral microtubules at an anterior cortical site by a localized minus-end directed motor. This would generate a torque on the centrosome/ nuclear complex and reel one of the centrosomes in the direction of the cortical site (Hyman 1989). 

Summary of Proposed Models for Microtubule Assembly from Depolymerized Microtubule Protein... 

This theory clearly predicts that the shape of the polymer length distribution curve determines the shape of the time course of depolymerization. For example Kristofferson et al. (1980) were able to show that apparent first-order depolymerization kinetics arise from length distributions which are nearly exponential. It should also be noted that the above theory helps one to gain a better feeling for the time course of cytoskeleton or mitotic apparatus disassembly upon cooling cells to temperatures which destabilize microtubules and effect unidirectional depolymerization. Likewise, the linear depolymerization kinetic model could be applied to the disassembly of bacterial flagella, muscle and nonmuscle F-actin, tobacco mosaic virus, hemoglobin S fibers, and other linear polymers to elucidate important rate parameters and to test the sufficiency of the end-wise depolymerization assumption in such cases. 

Wegner also treated the case wherein assembly is coupled to nucleotide hydrolysis. Here, we consider a slight modification of his model to deal with the microtubule process. Normally, the concentration of GTP is maintained by use of a GTP-regenerating system (MacNeal et ai, 1977), and the system at the steady-state plateau of assembly can be described as in Scheme II. Under these conditions, the assembly-disassembly reactions are no longer reversible, and the primed rate constants are used to emphasize that we are dealing with a different case. The rate equations for the two ends are now given as ... 

Though the above mechanism had value in describing the steady-state tubulin flux, Karr and Purich (1979) pointed out that a number of association-dissociation steps can occur for each net protomer addition. They found that the rate of isothermal dilution-induced disassembly of microtubules proceeded at rates 500- to 1000-fold greater than the observed treadmilling rate which itself corresponded to a turnover of about 7% of the tubulin pool/hour (Margolis and Wilson, 1978). Karr and Purich (1979) also proposed that the unidirectional treadmilling model be amended to account for the rapidity of on-off events at the polymer ends, and they offered the alternative mechanism presented here. 

The threshold concentration of monomer that must be exceeded for any observable polymer formation in a self-assembling system. In the context of Oosawa s condensation-equilibrium model for protein polymerization, the cooperativity of nucleation and the intrinsic thermodynamic instability of nuclei contribute to the sudden onset of polymer formation as the monomer concentration reaches and exceeds the critical concentration. Condensation-equilibrium processes that exhibit critical concentration behavior in vitro include F-actin formation from G-actin, microtubule self-assembly from tubulin, and fibril formation from amyloid P protein. Critical concentration behavior will also occur in indefinite isodesmic polymerization reactions that involve a stable template. One example is the elongation of microtubules from centrosomes, basal bodies, or axonemes. 

The generality of the end-wise depolymerization kinetic model is indicated by the comparison of the observed and predicted time-courses of cold-induced microtubule disassembly (Fig. 3). See Self-Assembly Protein Polymerization... 

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