The cellular mechanisms that maintain neuronal polarity

Bentley, Marvin; Banker, Gary

doi:10.1038/nrn.2016.100

Cited by 137 publications

(187 citation statements)

References 158 publications

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Section: Discussionmentioning

confidence: 99%

“…In contrast, KIF3AB is ubiquitously expressed including neurons (2-4, 34), but our best understanding of KIF3AB transport is for intraflagellar transport in cilia. One testable hypothesis for future investigation is whether KIF3AC and KIF3AB in neurons read the tubulin code differently based on posttranslational by guest on April 27, 2019 http://www.jbc.org/ Downloaded from 9 modifications of the axonal versus dendritic microtubules to bias selective transport of cargos to enter axons or dendrites (34,(53)(54)(55).In summary, mathematical modeling has provided new insights to understand the motile properties of KIF3AC and KIF3AB. These results revealed that microtubule association for KIF3AC and KIF3AB is an emergent property due to heterodimerization, and once in the processive run, the rates of the nucleotide-dependent transitions result from the relative intrinsic catalytic properties of the motor domains.…”

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confidence: 99%

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Kinesin-2 heterodimerization alters entry into a processive run along the microtubule but not stepping within the run

Quinn¹,

Howsmon

Hahn

et al. 2018

Journal of Biological Chemistry

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Keywords: computational biology, intracellular trafficking, intraflagellar transport, ciliogenesis, mathematical modeling, microtubule, neuron, presteady-state kinetics, ATPase, processivity ABSTRACTHeterodimeric KIF3AC and KIF3AB, two members of the mammalian kinesin-2 family, generate force for microtubule plus end-directed cargo transport. However, the advantage of heterodimeric kinesins over homodimeric ones is not well understood. We showed previously that microtubule association for entry into a processive run was similar in rate for KIF3AC and KIF3AB at ~7.0 µM -1 s -1 . Yet, for engineered homodimers of KIF3AA and KIF3BB, this constant is significantly faster at 11 µM -1 s -1 and much slower for KIF3CC at 2.1 µM -1 s -1. These results led us to hypothesize that heterodimerization of KIF3A with KIF3C and KIF3A with KIF3B altered the intrinsic catalytic properties of each motor domain. Here, we tested this hypothesis by using presteady-state stoppedflow kinetics and mathematical modeling. Surprisingly, the modeling revealed that the catalytic properties of KIF3A and KIF3B/C were altered upon microtubule binding, yet each motor domain retained its relative intrinsic kinetics for ADP release and subsequent ATP binding and the nucleotide-promoted transitions thereafter. These results are consistent with the interpretation that for KIF3AB, each motor head is catalytically similar and therefore each step is approximately equivalent. In contrast, for KIF3AC the results predict that the processive steps will alternate between a fast step for KIF3A followed by a slow step for KIF3C resulting in asymmetric stepping during a processive run. This study reveals the impact of heterodimerization of the motor polypeptides for microtubule association to start the processive run and the fundamental differences in the motile properties of KIF3C in comparison to KIF3A and KIF3B.Kinesin-2 is a unique family of processive kinesins because it contains both homodimeric and heterodimeric motors involved in microtubule plusend directed cargo transport (reviewed in (1-4)). The mammalian heterodimeric kinesins result from three gene products: KIF3A, KIF3B, and KIF3C to form heterodimeric . KIF3AB and its orthologs form a heterotrimeric complex by association with KAP, a distinctive http://www.jbc.org/cgi/doi/10.1074/jbc.RA118.002767 The latest version is at JBC Papers in Press. Published on July 10, 2018 as Manuscript RA118.002767 by guest on April 27, 2019 http://www.jbc.org/ Downloaded from 2 adaptor protein for cargo linkage because it is largely composed of armadillo repeats (10)(11)(12)(13)(14)(15). It is the armadillo repeats that provide specificity of the interaction between KIF3AB and KAP and between KIF3AB-KAP and its cargo. KIF3AB-KAP transports multimeric protein complexes (designated intraflagellar transport (IFT) particles) into the cilium and has also been linked to ciliadependent signal transduction pathways including the Hedgehog signaling pathway (16,17). Moreover, KIF3A, KIF3B, and KAP are all essential genes (18)...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Kinesin-2 heterodimerization alters entry into a processive run along the microtubule but not stepping within the run

Quinn¹,

Howsmon

Hahn

et al. 2018

Journal of Biological Chemistry

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“…Yet, in spite of similarities in sequence and structure, KIF3AC appears to function specifically in neurons whereas KIF3AB-KAP and KIF17 appear more ubiquitously expressed (4,5,12, 38). …”

Section: Kinesin-2 Subfamilymentioning

confidence: 99%

“…Why is KIF3C so slow and how is this property encoded? Lastly, we do not yet know if KIF3AB and KIF3AC read the tubulin code differently for selective transport to axons versus dendrites (12, 38, 103). There are many discoveries ahead waiting for novel experiments and innovative technologies.…”

Section: Concluding Remarks and Outstanding Questionsmentioning

confidence: 99%

“…The KIF3C L11 insert was also implicated in the ability of homodimeric KIF3CC to be targeted to microtubule plus ends and act as a potent catastrophe factor to promote microtubule dynamics. KIF3CC∆L11 lost the ability to promote catastrophe, suggesting that the loop L11 extension, unique to KIF3C is a structural motif required for regulation of microtubule dynamics by KIF3CC (51).Yet, in spite of similarities in sequence and structure, KIF3AC appears to function specifically in neurons whereas KIF3AB-KAP and KIF17 appear more ubiquitously expressed (4,5,12, 38). …”

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confidence: 99%

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Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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Kinesin-2s are major transporters of cellular cargoes. This subfamily contains both homodimeric kinesins whose catalytic domains result from the same gene product and heterodimeric kinesins with motor domains derived from two different gene products. In this review, we focus on the progress to define the biochemical and biophysical properties of the kinesin-2 family members. Our understanding of their mechanochemical capabilities has been advanced by the ability to identify the kinesin-2 genes in multiple species, expression and purification of these motors for single molecule and ensemble assays, and development of new technologies enabling quantitative measurements of kinesin activity with greater sensitivity.Kinesins constitute a superfamily of microtubule-based molecular motor enzymes that couple the chemical energy from ATP turnover to force production for diverse cellular functions (reviewed in (1-12)). Kinesins are classified into 15 different subfamilies, yet they share a structurally conserved kinesin motor domain (1,3,(13)(14)(15)(16). However, key amino acid residue changes can confer unique mechanochemical properties to each kinesin, which in turn specify cellular function. The N-terminal kinesins are composed of an N-terminal motor domain connected to a long a-helical region that dimerizes into a coiled-coil stalk that ends with a C-terminal domain that may interact with specific adaptor proteins for cargo linkage (Fig. 1). N-kinesin subfamilies include conventional kinesin-1, kinesin-2, kinesin-3, kinesin-5 Eg5/KSP, and kinesin-7 CENP-E, and all are best known for their roles in intracellular transport.N-kinesins carry cargo directionally toward the plus-end of microtubules, which are polymerized from ab-tubulin subunits to form a cylindrical polymer of 13 protofilaments. The kinesins are able to "read" the polarity of the microtubule because of the structural asymmetry of ab-tubulin subunits. The movement of N-kinesins is designated as "processive," which implies that upon microtubule collision, a single, dimeric kinesin steps continuously toward the microtubule plus end in an asymmetric hand-over-hand manner hydrolyzing one ATP per 8-nm step for hundreds of steps (17)(18)(19)(20)(21)(22). The 8-nm step size results from the distance between adjacent ab-tubulin dimers along the microtubule lattice. As Fig. 2 illustrates, a processive kinesin binds the microtubule and then goes through a series of structural transitions, each modulated by nucleotide state. To maintain a processive run with continuous stepping, the Kinesin-2 Molecular Motors 2ATPase cycle of each head remains out-of-phase with the other to avoid premature release if both heads exist in a microtubule weak binding state simultaneously. The degree of processivity, quantified by "run length," varies between kinesin subfamilies and is regulated by a series of "gating" mechanisms in which a chemical and/or mechanical requirement must be satisfied to proceed forward. There has been significant effort to define the determinants of ...

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Expressing Optogenetic Actuators Fused to N‐terminal Mucin Motifs Delivers Targets to Specific Subcellular Compartments in Polarized Cells

Wang,

Platz‐Baudin,

Noetzel

et al. 2023

Advanced Biology

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Optogenetics is a powerful approach in neuroscience research. However, other tissues of the body may benefit from controlled ion currents and neuroscience may benefit from more precise optogenetic expression. The present work constructs three subcellularly‐targeted optogenetic actuators based on the channelrhodopsin ChR2‐XXL, utilizing 5, 10, or 15 tandem repeats (TR) from mucin as N‐terminal targeting motifs and evaluates expression in several polarized and non‐polarized cell types. The modified channelrhodopsin maintains its electrophysiological properties, which can be used to produce continuous membrane depolarization, despite the expected size of the repeats. This work then shows that these actuators are subcellularly localized in polarized cells. In polarized epithelial cells, all three actuators localize to just the lateral membrane. The TR‐tagged constructs also express subcellularly in cortical neurons, where TR5‐ChR2XXL and TR10‐ChR2XXL mainly target the somatodendrites. Moreover, the transfection efficiencies are shown to be dependent on cell type and tandem repeat length. Overall, this work verifies that the targeting motifs from epithelial cells can be used to localize optogenetic actuators in both epithelia and neurons, opening epithelia processes to optogenetic manipulation and providing new possibilities to target optogenetic tools.

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The cellular mechanisms that maintain neuronal polarity

Cited by 137 publications

References 158 publications

Kinesin-2 heterodimerization alters entry into a processive run along the microtubule but not stepping within the run

Kinesin-2 heterodimerization alters entry into a processive run along the microtubule but not stepping within the run

Kinesin-2 motors: Kinetics and biophysics

Expressing Optogenetic Actuators Fused to N‐terminal Mucin Motifs Delivers Targets to Specific Subcellular Compartments in Polarized Cells

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