Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Abstract

ABD) preferentially engages actin in the presence of mechanical load across actin filaments (''mechanoaccumulation''), while vinculin's ABD does not. Simultaneous optical trapping and confocal microscopy experiments demonstrate that a load of 1pN across actin activates a-catenin ABD binding. Atomic-resolution cryo-EM structures of the metavinculin ABD-actin (2.9Å ) and a-catenin ABD-actin (3.2Å ) complexes demonstrate both ABDs undergo major conformational changes upon actin engagement, prominently at their N-and C-termini, and their C-terminal regions differentially refold to bind distinct sites on the filament surface. A C-terminal truncation of a-catenin's ABD constitutively binds actin regardless of force, and a chimeric protein of vinculin's ABD featuring a-catenin's flexible termini gains mechanoaccumulation activity, suggesting the a-catenin C-terminus-actin interaction is necessary and sufficient for mechanically regulated binding. This work, for the first time, establishes a force-regulated actin-binding mechanism in structural detail, and lays the groundwork for the rational design of therapeutics targeting cytoskeletal mechanotransduction pathways.