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Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

Ruensern Tan, Aileen J. Lam, Tracy Tan, Jisoo Han, Dan W. Nowakowski, Michael Vershinin, Sergi Simo, Kassandra M. Ori-McKenney, Richard J. McKenney

Preprint posted on September 22, 2018 https://www.biorxiv.org/content/early/2018/09/22/423376

Article now published in Nature Cell Biology at http://dx.doi.org/10.1038/s41556-019-0375-5

and

Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes

Valerie Siahaan, Jochen Krattenmacher, Amayra Hernandez-Vega, Anthony A Hyman, Stefan Diez, Zdenek Lansky, Marcus Braun

Preprint posted on September 22, 2018 https://www.biorxiv.org/content/early/2018/09/22/424374

Article now published in Nature Cell Biology at http://dx.doi.org/10.1038/s41556-019-0374-6

Islands on the highways! The microtubule-associated protein tau forms reversible islands on microtubules in vitro and modulates the behavior of motor proteins and severing enzymes.

Selected by Satish Bodakuntla

Context: Ever since the discovery of microtubule-associated proteins (MAPs) in the 1970s, tau has received particular interest as it is involved in a number of neurodegenerative diseases and undergoes diverse molecular behaviours (tau aggregation and tau phase separation droplets). While tau was shown to regulate microtubule interactions of several MAPs including motor proteins and severing enzymes, the underlying mechanisms remained largely elusive. In these preprints, the authors show that tau forms reversible condensates on the microtubules in vitro and reveal how these condensates regulate the microtubule interaction of severing enzymes and molecular motors.

Key findings: The authors used in vitro reconstitution assays and observed that tau binds microtubules in a non-homogenous manner, i.e. some regions of microtubules are densely decorated with tau molecules, termed ‘tau condensates’ or ‘tau islands’. These condensates can grow and shrink along the microtubule, merge with the nearby condensates and are reversible upon removal of tau from the solution. Consistent with earlier in vivo data showing that tau prevents microtubule severing, the authors observed that tau islands efficiently protect the microtubules from katanin and spastin mediated-severing. Interestingly, these tau islands selectively form barriers on microtubules to regulate the movement of molecular motors. While highly processive molecular motors, like dynein and kinesin-8 could efficiently pass through the condensates, kinesin-1 motors could not penetrate the tau islands. Overall, the authors present a novel idea that tau condensation is in fact a physiological form of tau self-association and thereby explain the physiological importance of tau oligomerization in mediating its functions.

Why this preprint is interesting: Microtubules, formed by well-conserved tubulin heterodimers, must functionally specialize to perform a plethora of diverse functions, which many times is attained by interacting with several MAPs. Strikingly, in these preprints, the authors go one step ahead and show how an individual MAP – tau – by forming two distinct phases spatially confers different properties to microtubules. Further, the observations made by the authors raise very intriguing questions for the microtubule community.

Questions the work raises: The preprints complement each other well to strengthen their hypothesis and to address possible questions in the scope of their study. That said, their results raise intriguing questions for the follow-up studies.

  1. Why do tau condensates form islands specifically in some regions of microtubules?
  2. Why does tau form condensates only on taxol-stabilised microtubules and not on GMP-CPP microtubules?
  3. Can other microtubule-associated proteins also form condensates or islands?

Tags: microtubule-associated proteins, microtubules, molecular motors, tau

Posted on: 12th December 2018 , updated on: 19th December 2018

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  • Author's response

    Richard J. McKenney shared about Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

    We appreciate the author’s interest in our work! We are especially excited by the finding that self-association of tau molecules, long thought to be a disease-specific event, may also be relevant to the physiological functions of tau molecules in cells. Our work reveals a novel, reversible form of tau self-association that appears distinct from the pathological aggregation typically observed in tauopathies. We hope this discovery opens up new avenues of thought and research about both the physiological and pathological states of the tau molecule in neurons.

    In regards to the author’s excellent questions:

    1. Why do tau condensates form islands specifically in some regions of microtubules?

    This is the most pressing question in our minds! We observed that, remarkably, tau condensates consistently appear at specific “hot-spots” on the microtubule lattice. We have hypothesized that these spots could reflect local changes in microtubule architecture or even damage to the lattice. The first idea is supported by other data in the paper showing that tau condensation is sensitive to both the nucleotide state and curvature of the microtubule lattice. Current experiments in the lab are focused on answering this question.

    1. Why does tau form condensates only on taxol-stabilised microtubules and not on GMP-CPP microtubules?

    Previous studies have suggested that tau behaves differently on GDP (facilitated by taxol in our experiments) versus GTP (mimicked by GMP-CPP) lattice architectures (Duan et al. JMB 2017, McVicker et al. JBC 2011). Our results build on these observations by directly visualizing the behavior of tau molecules on these two types of lattices. Surprisingly, we observed that tau condensation only occurs on the GDP (taxol) form of the lattice, suggesting that a change in lattice architecture is necessary to facilitate, or “gate” tau condensation. Recent high-resolution cryo-EM structures of GDP versus GTP microtubule lattices have revealed that the primary difference in lattice architecture lies in the inter-tubulin dimer distance (Zhang et al. PNAS, 2018). Thus we hypothesize that tau condensation is likely regulated by the spacing of the inter-dimer distance within the lattice. Biologically, this implies that tau condensation is spatially regulated away from the growing plus-ends of microtubules, which retain a GTP-tubulin cap, and possibly away from newly incorporated GTP-tubulin dimers along the lattice (Vemu et al. Science. 2018).

    1. Can other microtubule-associated proteins also form condensates or islands?

    This is an excellent question! There are hints of similar behavior in recent studies (Monroy et al. Nat. Commun. 2018), but a comprehensive analysis of how all MAPs behave on the microtubule lattice, both alone and in combination with other MAPs, is currently lacking. Single molecule imaging will be an excellent technique to answer this question in the near future, and we fully expect there to be more surprises along the way!

    and

    Marcus Braun shared about Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes

    Starting with our previous finding of tau liquid-liquid phase separation (Hernández-Vega, et al. 2017. “Local Nucleation of Microtubule Bundles Through Tubulin Concentration Into a Condensed Tau Phase.” Cell Reports 20 (10): 2304–12.), which demonstrated that the intrinsically disordered tau molecules can interact to form liquid drops of high-density tau, we wondered if the presence of pre-assembled microtubules could facilitate tau-tau interaction. We reasoned that individual tau proteins could interact more readily with each other when being tethered to the microtubule via their binding domains. During their diffusive exploration of the microtubule surface, we thought, the tau molecules, might bump into each other a lot more often than during 3D diffusion in solution. To our delight, we indeed found that the reduction in dimensionality from 3D to 2D diffusion resulted in the interaction of diffusive tau molecules leading to the formation of tau islands in absence of any crowding agents, at physiological ionic strengths and at nano-molar concentrations. The islands formed are not liquid (as tau associated with the islands is not diffusing), but rather solid (with the individual tau molecules being stationary), but very dynamic as they reversibly grow and shrink from their edges, depending on the tau concentration in solution. Our finding that these tau islands regulate the accessibility of the microtubule surface for kinesin molecular motors and the microtubule severing enzyme katanin, makes us confident that reversible island formation by intrinsically disordered MAPs will emerge as common means, in particular in the context of neuronal axons, where tau is present in vivo, to regulate microtubule accessibility for molecular motors and other associated proteins, thus governing motorized transport and cytoskeletal dynamics.

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