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      The mechanisms of microtubule catastrophe and rescue: implications from analysis of a dimer-scale computational model

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          Abstract

          ETOC: The behavior of a dimer-scale computational model predicts that short interprotofilament “cracks” (laterally unbonded regions between protofilaments) exist even at the tips of growing MTs and that rapid fluctuations in the depths of these cracks govern both catastrophe and rescue.

          Abstract

          Microtubule (MT) dynamic instability is fundamental to many cell functions, but its mechanism remains poorly understood, in part because it is difficult to gain information about the dimer-scale events at the MT tip. To address this issue, we used a dimer-scale computational model of MT assembly that is consistent with tubulin structure and biochemistry, displays dynamic instability, and covers experimentally relevant spans of time. It allows us to correlate macroscopic behaviors (dynamic instability parameters) with microscopic structures (tip conformations) and examine protofilament structure as the tip spontaneously progresses through both catastrophe and rescue. The model's behavior suggests that several commonly held assumptions about MT dynamics should be reconsidered. Moreover, it predicts that short, interprotofilament “cracks” (laterally unbonded regions between protofilaments) exist even at the tips of growing MTs and that rapid fluctuations in the depths of these cracks influence both catastrophe and rescue. We conclude that experimentally observed microtubule behavior can best be explained by a “stochastic cap” model in which tubulin subunits hydrolyze GTP according to a first-order reaction after they are incorporated into the lattice; catastrophe and rescue result from stochastic fluctuations in the size, shape, and extent of lateral bonding of the cap.

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          Most cited references60

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          Dynamic instability of microtubule growth.

          We report here that microtubules in vitro coexist in growing and shrinking populations which interconvert rather infrequently. This dynamic instability is a general property of microtubules and may be fundamental in explaining cellular microtubule organization.
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            Tracking the ends: a dynamic protein network controls the fate of microtubule tips.

            Microtubule plus-end tracking proteins (+TIPs) are a diverse group of evolutionarily conserved cellular factors that accumulate at the ends of growing microtubules. They form dynamic networks through the interaction of a limited set of protein modules, repeat sequences and linear motifs that bind to each other with moderate affinities. +TIPs regulate different aspects of cell architecture by controlling microtubule dynamics, microtubule interactions with cellular structures and signalling factors, and the forces that are exerted on microtubule networks.
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              Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau.

              Microtubule-associated proteins (MAP), such as tau, modulate the extent and rate of microtubule assembly and play an essential role in morphogenetic processes, such as axonal growth. We have examined the mechanism by which tau affects microtubule polymerization by examining the kinetics of microtubule assembly and disassembly through direct observation of microtubules using dark-field microscopy. Tau increases the rate of polymerization, decreases the rate of transit into the shrinking phase (catastrophe), and inhibits the rate of depolymerization. Tau strongly suppresses the catastrophe rate, and its ability to do so is independent of its ability to increase the elongation rate. Thus, tau generates a partially stable but still dynamic state in microtubules. This state is perturbed by phosphorylation by MAP2 kinase, which affects all three activities by lowering the affinity of tau for the microtubule lattice.
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                Author and article information

                Contributors
                Role: Monitoring Editor
                Journal
                Mol Biol Cell
                molbiolcell
                mbc
                Mol. Bio. Cell
                Molecular Biology of the Cell
                The American Society for Cell Biology
                1059-1524
                1939-4586
                15 February 2012
                : 23
                : 4
                : 642-656
                Affiliations
                [1] aDepartment of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556
                [2] bInterdisciplinary Center for the Study of Biocomplexity, University of Notre Dame, Notre Dame, IN 46556
                [3] cDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556
                [4] dDepartment of Computer Science and Engineering, University of Notre Dame, Notre Dame, IN 46556
                [5] eDepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 40202
                University of California, Davis
                Author notes

                *These authors contributed equally to this work.

                Present addresses: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

                Department of Computer Science, Eckerd College, St. Petersburg, FL 33711;

                §Department of Mathematics, University of Minnesota Twin Cities, Minneapolis, MN 55455.

                §§Address correspondence to: Holly Goodson ( hgoodson@ 123456nd.edu ).
                Article
                E11-08-0688
                10.1091/mbc.E11-08-0688
                3279392
                22190741
                4cbb09b8-154f-4318-965b-fdb1af33b63e
                © 2012 Margolin et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( http://creativecommons.org/licenses/by-nc-sa/3.0).

                “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.

                History
                : 12 August 2011
                : 30 November 2011
                : 13 December 2011
                Categories
                Articles
                Cytoskeleton

                Molecular biology
                Molecular biology

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