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Kinesin-5 Promotes Microtubule Nucleation and Assembly by Stabilizing a Lattice-Competent Conformation of Tubulin.
Chen GY
,
Cleary JM
,
Asenjo AB
,
Chen Y
,
Mascaro JA
,
Arginteanu DFJ
,
Sosa H
,
Hancock WO
.
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Besides sliding apart antiparallel microtubules during spindle elongation, the mitotic kinesin-5, Eg5, promotes microtubule polymerization, emphasizing its importance in mitotic spindle length control. Here, we characterize the Eg5microtubule polymerase mechanism by assessing motor-induced changes in the longitudinal and lateral tubulin-tubulin bonds that form the microtubule lattice. Isolated Eg5 motor domains promote microtubule nucleation, growth, and stability; thus, crosslinking tubulin by pairs of motor heads is not necessary for polymerase activity. Eg5 binds preferentially to microtubules over free tubulin, which contrasts with microtubule-depolymerizing kinesins that preferentially bind free tubulin over microtubules. Colchicine-like inhibitors that stabilize the bent conformation of tubulin allosterically inhibit Eg5 binding, consistent with a model in which Eg5 induces a curved-to-straight transition in tubulin. Domain swap experiments establish that the family-specific loop11-helix 4 junction, which resides near the nucleotide-sensing switch-II domain, is necessary and sufficient for the polymerase activity of Eg5. Thus, we propose a microtubule polymerase mechanism in which Eg5 at the plus-end promotes a curved-to-straight transition in tubulin that enhances lateral bond formation and thereby promotes microtubule growth and stability. One implication is that regulation of Eg5 motile properties by regulatory proteins or small molecule inhibitors could also have effects on intracellular microtubule dynamics.
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