Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau

Yunior Cabrales Fontela,Eckhard Mandelkow,Dietmar Riedel,Harindranath Kadavath,Markus Zweckstetter,Jacek Biernat

doi:10.1038/s41467-017-02230-8

Abstract

Microtubule-associated proteins regulate microtubule dynamics, bundle actin filaments, and cross-link actin filaments with microtubules. In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer’s disease. Here we provide insight into the nature of interaction between Tau and actin filaments. We show that Tau uses several short helical segments to bind in a dynamic, multivalent process to the hydrophobic pocket between subdomains 1 and 3 of actin. Although a single Tau helix is sufficient to bind to filamentous actin, at least two, flexibly linked helices are required for actin bundling. In agreement with a structural model of Tau repeat sequences in complex with actin filaments, phosphorylation at serine 262 attenuates binding of Tau to filamentous actin. Taken together the data demonstrate that bundling of filamentous actin and cross-linking of the cellular cytoskeleton depend on the metamorphic and multivalent nature of microtubule-associated proteins.

Highlights

Microtubule-associated proteins regulate microtubule dynamics, bundle actin filaments, and cross-link actin filaments with microtubules
A molecular understanding of the interaction of Microtubule-associated proteins (MAPs) with filamentous actin is complicated by the dynamic structure of microtubule-associated proteins15, 27
Tau-induced neurotoxicity is associated with increased filamentous actin (F-actin) levels22, and Tau-induced remodeling of the actin cytoskeleton can cause plasma membrane blebbing57

Summary

Introduction

Microtubule-associated proteins regulate microtubule dynamics, bundle actin filaments, and cross-link actin filaments with microtubules. Aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer’s disease. About the molecular nature of the Tau/F-actin complex, about the involved binding sites, the mechanism of F-actin bundling and the MAP-driven process of cross-linking of microtubules and actin filaments. A molecular understanding of the interaction of MAPs with filamentous actin is complicated by the dynamic structure of microtubule-associated proteins . We provide high-resolution information about the structural changes that occur when Tau binds to F-actin and show that conformational changes in specific regions, which are separated by flexible linkers, are responsible for bundling of actin filaments as well as for cross-linking of actin filaments with microtubules. Our results clarify the nature of interaction between actin and MAPs and the actin/microtubule crosstalk

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