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

DOI: 10.15252/embj.201797902 DOI Help

Authors: Selena G. Burgess (University of Leeds) , Manjeet Mukherjee (University of Leeds) , Sarah Sabir (University of Leeds) , Nimesh Joseph (Cancer Research UK Cambridge Institute, University of Cambridge) , Cristina Gutiérrez‐caballero (University of Warwick) , Mark W. Richards (University of Leeds) , Nicolas Huguenin‐dezot (Medical Research Council Laboratory of Molecular Biology) , Jason W. Chin (Medical Research Council Laboratory of Molecular Biology) , Eileen J. Kennedy (University of Georgia) , Mark Pfuhl (Kings College London) , Stephen J. Royle (University of Warwick) , Fanni Gergely (Cancer Research UK Cambridge Institute, University of Cambridge) , Richard Bayliss (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal

State: Published (Approved)
Published: March 2018

Open Access Open Access

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.

Journal Keywords: disorder–order transition; intrinsically disordered protein; phosphorylation; protein kinase; protein–protein interaction

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
embj.201797902.full.pdf