Kinesin’s light chains inhibit the head- and microtubule-binding activity of its tail

Wong, Yao Liang; Rice, Sarah E.

doi:10.1073/pnas.1005854107

Cited by 45 publications

(49 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Biochemical studies mapped this site to positively charged residues at the extreme C terminus of the heavy chain (16)(17)(18). Based on these studies, we hypothesized that KHC engages in MT sliding by binding one MT with its C-terminal MTbinding site while walking along a second MT using its motor domain.…”

mentioning

confidence: 99%

Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

Winding

Kelliher

Lü

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

View full text Add to dashboard Cite

The plus-end microtubule (MT) motor kinesin-1 is essential for normal development, with key roles in the nervous system. Kinesin-1 drives axonal transport of membrane cargoes to fulfill the metabolic needs of neurons and maintain synapses. We have previously demonstrated that kinesin-1, in addition to its well-established role in organelle transport, can drive MT-MT sliding by transporting "cargo" MTs along "track" MTs, resulting in dramatic cell shape changes. The mechanism and physiological relevance of this MT sliding are unclear. In addition to its motor domain, kinesin-1 contains a second MT-binding site, located at the C terminus of the heavy chain. Here, we mutated this C-terminal MT-binding site such that the ability of kinesin-1 to slide MTs is significantly compromised, whereas cargo transport is unaffected. We introduced this mutation into the genomic locus of kinesin-1 heavy chain (KHC), generating the Khc mutA allele. Khc mutA neurons displayed significant MT sliding defects while maintaining normal transport of many cargoes. Using this mutant, we demonstrated that MT sliding is required for axon and dendrite outgrowth in vivo. Consistent with these results, Khc mutA flies displayed severe locomotion and viability defects. To test the role of MT sliding further, we engineered a chimeric motor that actively slides MTs but cannot transport organelles. Activation of MT sliding in Khc mutA neurons using this chimeric motor rescued axon outgrowth in cultured neurons and in vivo, firmly establishing the role of sliding in axon outgrowth. These results demonstrate that MT sliding by kinesin-1 is an essential biological phenomenon required for neuronal morphogenesis and normal nervous system development.kinesin-1 | microtubules | Drosophila | axon outgrowth | dendrite outgrowth N eurons are the basic unit of the nervous system, forming vast networks throughout the body that communicate using receptorligand machinery located in long cellular projections called axons and dendrites. Learning how these processes form is key to understanding the early development and pathology of the nervous system. Microtubules (MTs) and actin microfilaments have been implicated in neurite outgrowth, with many studies focusing on the growth cone at the tip of the axon. Previous models suggest that the driving forces for neurite outgrowth are MT polymerization and the treadmilling of F-actin (1, 2). However, other studies demonstrate that F-actin is dispensable to outgrowth and neurites extend even in the absence of F-actin (3-5).Our group has found that the motor protein kinesin-1 can rearrange the MT network by sliding MTs against each other (6). We have shown that kinesin-1 is required for MT sliding in cultured neurons and kinesin-1 depletion inhibits both neurite outgrowth and regeneration (7,8). Additionally, we have observed MT sliding in axons as well as MTs pushing on the axon tip (9). Recent studies from other groups have also implicated MT translocation in axon extension and dendritic organization (10-12). Based on th...

show abstract

mentioning

confidence: 99%

Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

Winding

Kelliher

Lü

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

View full text Add to dashboard Cite

show abstract

“…5C), although all four YFP constructs were present in both dendrites and axons in transfected neurons. Whereas the tailmicrotubule binding is disrupted by KLC (Wong and Rice, 2010) and Kv3 T1 domain (Fig. 4G), only coexpression of YFP-KLC1 but not YFP-Kv3.1b brought CFP-Tail into distal axons, suggesting binding to microtubules may not be the only mechanism to trap the tail domain in somatodendritic regions.…”

Section: Kv3 Clusters and Activates Kif5 Motors 2031mentioning

confidence: 99%

“…6). In contrast to the sophisticated roles of KLC1 (Wong and Rice, 2010;Cai et al, 2007), the action of Kv3.1 appears to be straightforward, which is to activate and cluster KIF5B motors. We also examined two other KIF5-binding proteins, SNAP25 and VAMP2.…”

Section: Different Cargos Ride Kif5 Motors Differently Suggesting Camentioning

confidence: 99%

“…Although KLC1 was also shown to release the tail-motor domain binding and tailmicrotubule binding (Wong and Rice, 2010), Kv3.1 and KLC1 differ in multiple ways in regulating KIF5 motor activity. First, they bind to different regions in KIF5B tail (Fig.…”

Section: Different Cargos Ride Kif5 Motors Differently Suggesting Camentioning

confidence: 99%

“…Kv3.1 T1 competes with the KIF5B motor domain and microtubules but not with KLC1 for binding to KIF5B tail KIF5 C-terminal tail domains contain overlapping binding sites for cargo recognition, auto-inhibition, and for interactions with myosin and microtubules (Twelvetrees et al, 2010;Wong and Rice, 2010;Xu et al, 2010;Andrews et al, 1993;Diefenbach et al, 1998;Coy et al, 1999;Friedman and Vale, 1999;Huang et al, 1999;Hackney and Stock, 2000;Setou et al, 2002;Cai et al, 2005;Glater et al, 2006) (Fig. 4A).…”

Section: Kv3 Clusters and Activates Kif5 Motors 2029mentioning

confidence: 99%

See 2 more Smart Citations

Activation of conventional kinesin motors in clusters by shaw voltage-gated potassium channels

Barry

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

SummaryThe conventional kinesin motor transports many different cargos to specific locations in neurons. How cargos regulate motor function remains unclear. Here we focus on KIF5, the heavy chain of conventional kinesin, and report that the Kv3 (Shaw) voltage-gated K + channel, the only known tetrameric KIF5-binding protein, clusters and activates KIF5 motors during axonal transport. Endogenous KIF5 often forms clusters along axons, suggesting a potential role of KIF5-binding proteins. Our biochemical assays reveal that the highaffinity multimeric binding between the Kv3.1 T1 domain and KIF5B requires three basic residues in the KIF5B tail. Kv3.1 T1 competes with the motor domain and microtubules, but not with kinesin light chain 1 (KLC1), for binding to the KIF5B tail. Live-cell imaging assays show that four KIF5-binding proteins, Kv3.1, KLC1 and two synaptic proteins SNAP25 and VAMP2, differ in how they regulate KIF5B distribution. Only Kv3.1 markedly increases the frequency and number of KIF5B-YFP anterograde puncta. Deletion of Kv3.1 channels reduces KIF5 clusters in mouse cerebellar neurons. Therefore, clustering and activation of KIF5 motors by Kv3 regulate the motor number in carrier vesicles containing the channel proteins, contributing not only to the specificity of Kv3 channel transport, but also to the cargo-mediated regulation of motor function.

show abstract

Atlas stumbled: Kinesin light chain‐1 variant E triggers a vicious cycle of axonal transport disruption and amyloid‐β generation in Alzheimer's disease

2014

View full text Add to dashboard Cite

Substantial evidence implicates fast axonal transport (FAT) defects in neurodegeneration. In Alzheimer's disease (AD), it is controversial whether transport defects cause or arise from amyloid-β (Aβ)-induced toxicity. Using a novel, unbiased genetic screen, Morihara et al. identified kinesin light chain-1 splice variant E (KLC1vE) as a modifier of Aβ accumulation. Here, we propose three mechanisms to explain this causal role. First, KLC1vE reduces APP transport, leading to Aβ accumulation. Second, reduced transport of APP by KLC1vE triggers an ER stress response that activates the amyloidogenic pathway. Third, KLC1vE impairs transport of other KLC1 cargos that regulate amyloidogenesis, promoting Aβ retention within the secretory pathway. Collectively, KLC1vE perpetuates a vicious cycle of Aβ generation, kinase dysregulation, and global FAT impairment that inevitably leads to cellular toxicity. These concepts implicate alternative splicing of KLC1 in AD and suggest that the reciprocal influence of transport mechanisms on disease states contributes to neurodegeneration.

show abstract

Kinesin’s light chains inhibit the head- and microtubule-binding activity of its tail

Cited by 45 publications

References 51 publications

Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

Role of kinesin-1–based microtubule sliding in Drosophila nervous system development

Activation of conventional kinesin motors in clusters by shaw voltage-gated potassium channels

Atlas stumbled: Kinesin light chain‐1 variant E triggers a vicious cycle of axonal transport disruption and amyloid‐β generation in Alzheimer's disease

Contact Info

Product

Resources

About