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

TY - JOUR

T1 - Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix

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

Y1 - 2018/4/13

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

KW - phosphorylation

KW - protein kinase

KW - protein–protein interaction

UR - https://www.scopus.com/pages/publications/85043303634

U2 - 10.15252/embj.201797902

DO - 10.15252/embj.201797902

M3 - Article

AN - SCOPUS:85043303634

SN - 0261-4189

VL - 37

JO - EMBO Journal

JF - EMBO Journal

IS - 8

M1 - e97902

ER -