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

Siahaan, Valerie; Krattenmacher, Jochen; Hyman, Anthony; Diez, Stefan; Hernández-Vega, Amayra; Lánský, Zdeněk; Braun, Marcus

doi:10.1038/s41556-019-0374-6

Cited by 117 publications

(116 citation statements)

References 36 publications

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“…Strikingly, addition of mCherry-TRAK1 increased the median run length of KIF5B∆-mCherry in the presence of the roadblocks about two-fold, to 1.12 µm (CI95 ii) To test if TRAK1 anchoring promotes KIF5B∆-GFP processivity also in the presence of intrinsically disordered, microtubule-bound, neuronal proteins that regulate axonal transport, we next used the unstructured, microtubule-associated mCherry-labelled protein tau (tau-mCherry). Tau forms cohesive islands of high density on the microtubule surface 52 , preventing kinesin-1 from walking into regions of microtubules covered by these islands 53 (Figure 4d Taken together, our results show that TRAK1 promotes long range KIF5B∆-based transport on crowded microtubules. 9 Finally, we asked if the KIF5B-TRAK1 transport complex characterized above can transport mitochondria.…”

Section: Trak1 Increases the Processivity Of Kif5bmentioning

confidence: 57%

“…Knockdown of TRAK1 was demonstrated to result in neurodegeneration, which was suppressed by an additional knockdown of tau 66 . In vitro, tau cooperatively forms cohesive islands on the microtubule surface, preventing kinesin-1 driven transport within the tau island-coated regions of microtubules 52,53 . Our results show that TRAK1 enables KIF5B entering regions covered with tau islands, increasing the probability of KIF5B to traverse tau islands and thus overriding the tau island-dependent blockade of kinesin-1-driven transport.…”

Section: Discussionmentioning

confidence: 99%

“…By this mechanism KIF5B can sequentially displace the tau microtubule-binding repeats, enabling motion through the island-covered microtubule region. Similarly, Kip3, a super-processive kinesin known to pause in the absence of an adjacent free binding site 67 , traverses cohesive tau islands efficiently 53 . Other neuronal intrinsically disordered microtubule-associated proteins are likely to form similar cohesive islands on microtubules 68 .…”

Section: Discussionmentioning

confidence: 99%

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

Henrichs

Grycová

Bařinka

et al. 2020

Preprint

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Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential processes including neuronal activity. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under protein crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in crowded intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases its robustness of stepping in protein crowding conditions. Interaction with TRAK1 i) facilitated kinesin-1 navigation around obstacles, ii) increased the probability of kinesin-1 passing through cohesive envelopes of tau and iii) increased 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. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.

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Section: Trak1 Increases the Processivity Of Kif5bmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Henrichs

Grycová

Bařinka

et al. 2020

Preprint

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“…In particular, enclosing microtubules with cohesive patches of intrinsically disordered microtubule-associated proteins like tau can prevent kinesin stepping in the covered microtubule regions altogether [30]. Microtubule-binding accessory proteins increase the processivity of kinesins allowing them to move efficiently in tau-covered regions [29].…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced processivity enhances kinesin motility in crowded environments [29], for example the super processive kinesin-8 Kip3 molecules are able to move through islands of densely-packed tau molecules enveloping the microtubule surface, which hinder the motility of the less processive kinesin-1 [30]. To test if anchoring via the disordered domain might enhance the processivity of Kif14 stepping under such extreme crowding conditions, we formed tau cohesive islands and observed movement of Kif14 molecules within and outside of the islands.…”

Section: Enhanced Kif14 Processivity Enables Stepping In Crowded Envimentioning

confidence: 99%

Intrinsically disordered domain of kinesin-3 Kif14 enables unique functional diversity

Zhernov

Diez

Braun

et al. 2020

Preprint

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In addition to their force-generating motor domains, kinesin motor proteins feature various accessory domains enabling them to fulfil a variety of functions in the cell. Human kinesin-3, Kif14, localizes to the midbody of the mitotic spindle and is involved in the progression of cytokinesis. The specific motor properties enabling Kif14's cellular functions, however, remain unknown. Here, we show in vitro that it is the intrinsically disordered N-terminal domain of Kif14 that enables unique functional diversity of the motor. Using single molecule TIRF microscopy we observed that the presence of the disordered domain i) increased the Kif14 run-length by an order of magnitude, rendering the motor super-processive and enabling the motor to pass through highly crowded microtubule areas shielded by cohesive layers of microtubule-associated protein tau, which blocks less processive motors ii) enabled robust, autonomous Kif14 tracking of growing microtubule tips, independent of microtubule end-binding (EB) proteins and iii) enabled Kif14 to crosslink parallel microtubules and to drive the relative sliding of antiparallel ones. We explain these features of Kif14 by the observed increased affinity of the disordered domain for GTP-like tubulin and the observed diffusible interaction of the disordered domain with the microtubule lattice. We hypothesize that the disordered domain tethers the motor domain to the microtubule forming a diffusible foothold. We suggest that the intrinsically disordered N-terminal anchoring domain of Kif14 is a regulatory hub supporting the various cellular functions of Kif14 by tuning the motor's interaction with microtubules.

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Protein Condensation, Cellular Organization, and Spatiotemporal Regulation of Cytoplasmic Properties

Tartwijk

Kaminski

2022

Advanced Biology

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These folds are determined by both protein sequence and solvent properties, and determine protein function. [2] Therefore, the diversity of protein folds in cells allows them to carry out a range of functions, such as catalysis of different reactions. Functional versatility within polypeptide chains is further increased through the presence of multiple independently folding sequences, defined as domains, each associated with distinct functions, such as dimerization or responsiveness to a regulator. However, it is now recognized that some proteins do not have defined conformations, or feature domains that are intrinsically disordered (intrinsically disordered regions, IDRs), and that these confer function by mediating context-dependent proteinprotein interactions. [3] The concept of self-organization of proteins is also applied to assemblies of multiple proteins, in which case it refers to formation of dynamic multi-component structures, [4] including certain oligomeric complexes, filaments, and phase-separated assemblies. In phase-separated assemblies, of which a range exist, IDR-containing proteins form a dense phase within the cytoplasm, commonly referred to as biomolecular condensates. [5] As for folds, the formation of these assemblies depends both on interactions between the phase-separating proteins, which can be mediated by their IDRs, and between these proteins and the surrounding solution. Within the cytoplasm, these phase-separated "droplets" commonly contain RNA, in which case they are referred to as ribonucleoprotein (RNP) granules. They can be considered to have "emergent properties:" certain characteristics can be ascribed to assemblies that are not properties of individual constituent proteins. [6] For instance, biomolecular condensates can display liquid-like properties such as fusion and wetting, which led to their identification as phase-separated droplets. [7] These properties allow them to function as dynamic membraneless organelles, or compartments. This compartmentalization is commonly referred to as occurring on the "mesoscale," which is defined as that range of lengths larger than the size of individual molecular machinery such as ribosomes, but smaller than that of the whole cell. [8] The sensitivity of protein folds and macromolecular interactions to local environmental conditions confers both regulatory potential and risk of loss of function in "extreme" conditions. This regulatory potential is exemplified by and has beenThe cytoplasm is an aqueous, highly crowded solution of active macromolecules. Its properties influence the behavior of proteins, including their folding, motion, and interactions. In particular, proteins in the cytoplasm can interact to form phase-separated assemblies, so-called biomolecular condensates. The interplay between cytoplasmic properties and protein condensation is critical in a number of functional contexts and is the subject of this review. The authors first describe how cytoplasmic properties can affect protein behavior, in particular condensate formation...

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

Cited by 117 publications

References 36 publications

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

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

Intrinsically disordered domain of kinesin-3 Kif14 enables unique functional diversity

Protein Condensation, Cellular Organization, and Spatiotemporal Regulation of Cytoplasmic Properties

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