Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix

Selena G. Burgess; Manjeet Mukherjee; Sarah Sabir; Nimesh Joseph; Cristina Gutiérrez-Caballero; Mark W. Richards; Nicolas Huguenin-Dezot; Jason W. Chin; Eileen J. Kennedy; Mark Pfuhl; Stephen J. Royle; Fanni Gergely; Richard Bayliss

doi:10.15252/embj.201797902

Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix

Selena G. Burgess, Manjeet Mukherjee, Sarah Sabir, Nimesh Joseph, Cristina Gutiérrez-Caballero, Mark W. Richards, Nicolas Huguenin-Dezot, Jason W. Chin, Eileen J. Kennedy, Mark Pfuhl, Stephen J. Royle, Fanni Gergely, Richard Bayliss^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding.

Original language	English
Article number	e97902
Journal	EMBO Journal
Volume	37
Issue number	8
Early online date	6 Mar 2018
DOIs	https://doi.org/10.15252/embj.201797902
Publication status	Published - 13 Apr 2018

Keywords

disorder–order transition
intrinsically disordered protein
phosphorylation
protein kinase
protein–protein interaction

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10.15252/embj.201797902Licence: CC BY

Mitotic spindle association of TACC3 requires_PFUHL_Publishedonline6March2018_GOLD VoR (CC BY)Final published version, 3.29 MBLicence: CC BY

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Burgess, S. G., Mukherjee, M., Sabir, S., Joseph, N., Gutiérrez-Caballero, C., Richards, M. W., Huguenin-Dezot, N., Chin, J. W., Kennedy, E. J., Pfuhl, M., Royle, S. J., Gergely, F., & Bayliss, R. (2018). Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix. EMBO Journal, 37(8), Article e97902. https://doi.org/10.15252/embj.201797902

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abstract = "Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding.",

keywords = "disorder–order transition, intrinsically disordered protein, phosphorylation, protein kinase, protein–protein interaction",

author = "Burgess, {Selena G.} and Manjeet Mukherjee and Sarah Sabir and Nimesh Joseph and Cristina Guti{\'e}rrez-Caballero and Richards, {Mark W.} and Nicolas Huguenin-Dezot and Chin, {Jason W.} and Kennedy, {Eileen J.} and Mark Pfuhl and Royle, {Stephen J.} and Fanni Gergely and Richard Bayliss",

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AU - Burgess, Selena G.

AU - Mukherjee, Manjeet

AU - Sabir, Sarah

AU - Joseph, Nimesh

AU - Gutiérrez-Caballero, Cristina

AU - Richards, Mark W.

AU - Huguenin-Dezot, Nicolas

AU - Chin, Jason W.

AU - Kennedy, Eileen J.

AU - Pfuhl, Mark

AU - Royle, Stephen J.

AU - Gergely, Fanni

AU - Bayliss, Richard

PY - 2018/4/13

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N2 - Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding.

AB - Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding.

KW - disorder–order transition

KW - intrinsically disordered protein

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Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix

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