TOG-tubulin binding specificity promotes microtubule dynamics and mitotic spindle formation

The Journal of Cell Biology
Amy E Byrnes, Kevin C Slep

Abstract

XMAP215, CLASP, and Crescerin use arrayed tubulin-binding tumor overexpressed gene (TOG) domains to modulate microtubule dynamics. We hypothesized that TOGs have distinct architectures and tubulin-binding properties that underlie each family's ability to promote microtubule polymerization or pause. As a model, we investigated the pentameric TOG array of a Drosophila melanogaster XMAP215 member, Msps. We found that Msps TOGs have distinct architectures that bind either free or polymerized tubulin, and that a polarized array drives microtubule polymerization. An engineered TOG1-2-5 array fully supported Msps-dependent microtubule polymerase activity. Requisite for this activity was a TOG5-specific N-terminal HEAT repeat that engaged microtubule lattice-incorporated tubulin. TOG5-microtubule binding maintained mitotic spindle formation as deleting or mutating TOG5 compromised spindle architecture and increased the mitotic index. Mad2 knockdown released the spindle assembly checkpoint triggered when TOG5-microtubule binding was compromised, indicating that TOG5 is essential for spindle function. Our results reveal a TOG5-specific role in mitotic fidelity and support our hypothesis that architecturally distinct TOGs arranged in a se...Continue Reading

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Citations

Jun 1, 2018·Molecular Biology of the Cell·Shreoshi MajumdarLuke M Rice
Jul 20, 2019·PloS One·Jonathan B Leano, Kevin C Slep
Feb 23, 2020·The Journal of Biological Chemistry·Mark E Zweifel, Naomi Courtemanche
Jun 7, 2018·Acta Crystallographica. Section D, Structural Biology·Joseph AthertonCarolyn A Moores
Aug 21, 2020·Proceedings of the National Academy of Sciences of the United States of America·Pavel FilipčíkPeter D Mace
Dec 31, 2020·ELife·Jacob A HermanSue Biggins
Nov 8, 2020·Current Opinion in Cell Biology·Ryoma OhiMarija Zanic
Nov 16, 2020·Current Opinion in Cell Biology·Peng LiuElmar Schiebel
Oct 17, 2020·FEBS Letters·Geneviève Fourel, Cécile Boscheron
Jun 10, 2020·Current Biology : CB·Kevin C Slep
Aug 20, 2021·Nature Reviews. Molecular Cell Biology·Nikita B Gudimchuk, J Richard McIntosh

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Methods Mentioned

BETA
transfection
circular dichroism
light scattering
single crystal diffraction
PCR
transfections

Software Mentioned

XDS
phenix
plus
Dali
NIS Elements
GraphPad
Fiji
Prism
CLUSTALW
MTrackJ

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