Tau is an intrinsically disordered microtubule-associated protein (MAP) implicated in neurodegenerative disease. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive 'envelopes' around microtubules. Envelopes differentially regulate lattice accessibility for other MAPs, but the mechanism of envelope formation remains unclear. Here we find that tau envelopes form cooperatively, locally altering the spacing of tubulin dimers within the microtubule lattice. Envelope formation compacted the underlying lattice, whereas lattice extension induced tau envelope disassembly. Investigating other members of the tau family, we find that MAP2 similarly forms envelopes governed by lattice spacing, whereas MAP4 cannot. Envelopes differentially biased motor protein movement, suggesting that tau family members could spatially divide the microtubule surface into functionally distinct regions. We conclude that the interdependent allostery between lattice spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.

• MeSH
• lidé MeSH
• mikrotubuly metabolismus   MeSH
• neurodegenerativní nemoci * metabolismus   MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• proteiny tau * metabolismus   MeSH
• proteiny metabolismus   MeSH
• tubulin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• proteiny asociované s mikrotubuly MeSH
• proteiny tau * MeSH
• proteiny MeSH
• tubulin MeSH

Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential cellular processes. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases robustness of kinesin-1 stepping on crowded microtubule surfaces. Interaction with TRAK1 i) facilitates kinesin-1 navigation around obstacles, ii) increases the probability of kinesin-1 passing through cohesive islands of tau and iii) increases the run length of kinesin-1 in cell lysate. We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. Furthermore, TRAK1 enables mitochondrial transport in vitro. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.

• MeSH
• adaptorové proteiny vezikulární transportní genetika   izolace a purifikace   metabolismus   MeSH
• fluorescenční mikroskopie MeSH
• kineziny genetika   izolace a purifikace   metabolismus   MeSH
• luminescentní proteiny genetika   metabolismus   MeSH
• mikrotubuly metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proteiny tau genetika   metabolismus   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• vnitřně neuspořádané proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny vezikulární transportní MeSH
• KIF5B protein, human MeSH Prohlížeč
• kineziny MeSH
• luminescentní proteiny MeSH
• proteiny tau MeSH
• rekombinantní proteiny MeSH
• TRAK1 protein, human MeSH Prohlížeč
• vnitřně neuspořádané proteiny MeSH