Microtubules gate tau condensation to spatially regulate microtubule functions

Abstract

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer's disease and other dementias 1 , yet the physiological state of tau molecules within cells remains unclear. Using single molecule imaging, we directly observe that the microtubule lattice regulates reversible tau self-association, leading to localized, dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of microtubule severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible selfassociation of tau molecules, gated by the microtubule lattice, is an important mechanism of tau's biological functions, and that oligomerization of tau is a common property shared between the physiological and disease forms of the molecule.

Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments

“…Knockdown of TRAK1 was demonstrated to result in neurodegeneration, which was suppressed by an additional knockdown of tau 44 . In vitro, tau cooperatively forms cohesive islands on the microtubule surface, preventing kinesin-1 stepping within the tau island-coated regions of microtubules 32,34 . Our results show that the combined affinity of TRAK1 and KIF5B enables the complex to enter regions covered with cohesive tau islands, increasing the probability of KIF5B traversing them and thus overriding the tau island-dependent blockade of kinesin-1-driven transport (schematically shown in Fig.…”

“…In vitro experiments demonstrate that crowding strongly impedes kinesin-1-driven transport through a drastic reduction of kinesin-1 processivity [25][26][27][28] . One of the key regulators of microtubule-based trafficking in neurons, the intrinsically disordered protein tau [29][30][31] , can form densely crowded cohesive islands on microtubules, which strongly impede kinesin-1 motility [32][33][34] . To enable robust long-range kinesin-1-driven transport in cells, additional mechanisms, complementary to the coupling of multiple molecular motors, are thus likely required to overcome the hindering effect of crowding on the microtubule surface.…”

“…TRAK1 promotes KIF5B processivity in cohesive islands of tau. The intrinsically disordered microtubule-associated protein tau can regulate microtubule-based transport by forming cohesive islands on microtubules, strongly impeding kinesin-1 motility 32,34 . Since we observed that TRAK1 increased the processivity of KIF5B, we wondered whether TRAK1 can extend the movement range of kinesin-1 within tau islands.…”

Microtubule-Associated Proteins: Structuring the Cytoskeleton

“…On the mechanistic side, MAPs might physically impede motors or severing enzymes to interact with microtubules in regions densely decorated with MAPs. The recently discovered tau islands that stall kinesin motility provide a first model for a mechanism that could potentially shield microtubule stretches in cells [120,121]. However, there are multiple other mechanisms by which MAPs could influence the function of the microtubule cytoskeleton.…”

Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation

“…Although Cavin1 and CAV1 are associated together in caveolae, it remains unclear whether they interact with each other via direct protein-protein interactions. CAV1 has a unique structural domain architecture shared with other caveolins, consisting of an N-terminal disordered region (DR) (1-60), followed by an oligomerization domain (OD) (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80), scaffolding domain (CSD) (81-100), intramembrane domain (IMD) (101-133) and a C-terminal membrane associated a-helical domain (134-179) ( Fig. 3A; Fig.…”