Homodimeric Kinesin-2 KIF3CC Promotes Microtubule Dynamics

Guzik-Lendrum, Stephanie; Rayment, Ivan; Gilbert, Susan P.

doi:10.1016/j.bpj.2017.09.015

Cited by 13 publications

(12 citation statements)

References 41 publications

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“…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).…”

Section: Kinesin-2 Subfamilymentioning

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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Section: Kinesin-2 Subfamilymentioning

confidence: 99%

“…KIF3B does not form heterodimers with . Moreover, multiple studies showed that heterodimerization was preferential over homodimer formation (43,46,48,49) although there is evidence for an injury-specific homodimer of KIF3CC in neurons (45,47,50,51).KIF3AB forms a heterotrimeric complex by association with KAP ( Fig. 1, ( 36,[52][53][54]).…”

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Kinesin-2 motors: Kinetics and biophysics

Gilbert

Guzik-Lendrum

Rayment

2018

Journal of Biological Chemistry

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“…In addition, KIF3C exhibits a signature motif conserved in mammals, a 25-residue insert in loop L11 of the catalytic motor domain, which is enriched in glycines and serines, and this L11 insert is not present in other kinesins regardless of species (7,(33)(34)(35). The distinctive L11 domain of KIF3C has been implicated in regulating processivity for KIF3AC (35) and microtubule dynamics for homodimeric KIF3CC (36).…”

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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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“…As referred to above, in C. elegans mechanosensory axons, the kinesin‐13 family member KLP‐7 is downregulated after injury leading to an increased number of dynamic growing microtubules at the injury site (Ghosh‐Roy et al, ). Conversely, in in vitro assays, the kinesin‐2 family member KIF3C was identified as a key regulator of axon regeneration as it acts as an injury‐specific kinesin with microtubule‐destabilizing function (Guzik‐Lendrum et al, ), capable of promoting microtubule catastrophe (Guzik‐Lendrum et al, , Guzik‐Lendrum et al, ). KIF3C depletion in adult neurons leads to an increase in stable and looped microtubules and delayed axon regeneration (Guzik‐Lendrum et al, ).…”

Section: The Local Modulation Of Microtubule Dynamics Is Crucial For mentioning

confidence: 99%

Neuronal Intrinsic Regenerative Capacity: The Impact of Microtubule Organization and Axonal Transport

Murillo

Sousa

2018

Developmental Neurobiology

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In the adult vertebrate central nervous system, axons generally fail to regenerate. In contrast, peripheral nervous system axons are able to form a growth cone and regenerate upon lesion. Among the multiple intrinsic mechanisms leading to the formation of a new growth cone and to successful axon regrowth, cytoskeleton organization and dynamics is central. Here we discuss how multiple pathways that define the regenerative capacity converge into the regulation of the axonal microtubule cytoskeleton and transport. We further explore the use of dorsal root ganglion neurons as a model to study the neuronal regenerative ability. Finally, we address some of the unanswered questions in the field, including the mechanisms by which axonal transport might be modulated by injury, and the relationship between microtubule organization, dynamics, and axonal transport. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.

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Homodimeric Kinesin-2 KIF3CC Promotes Microtubule Dynamics

Cited by 13 publications

References 41 publications

Kinesin-2 motors: Kinetics and biophysics

Kinesin-2 motors: Kinetics and biophysics

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

Neuronal Intrinsic Regenerative Capacity: The Impact of Microtubule Organization and Axonal Transport

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