KIF5C S176 Phosphorylation Regulates Microtubule Binding and Transport Efficiency in Mammalian Neurons

Padzik, Artur; Deshpande, Prasannakumar; Hollós, Patrik; Franker, Mariella A.M.; Rannikko, Emmy Helena; Cai, Dawen; Prus, Piotr; Mågård, Mats; Westerlund, Nina; Verhey, Kristen J.; James, Peter; Hoogenraad, Casper C.; Coffey, Eleanor T.

doi:10.3389/fncel.2016.00057

Cited by 30 publications

(24 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the spatial relationship between mitochondria and microtubules is not affected by H 2 O 2 (Fig 2G), we reasoned that the activity of one of these 2 components could be the target of p38 for achieving ROS-induced inhibition of motility. Kinesin KIF5C has been already described as target of p38 (Morfini et al, 2013): phosphorylation of its serine residue in position 176 regulates cargo transport by promoting disengagement of the motor from microtubule tracks (Padzik et al, 2016). Kif5B, one of the kinesin responsible for movements of mitochondria (Tanaka et al, 1998) together with Kif1B and KLP (Nangaku et al, 1994; Tanaka et al, 2011), belongs to the same kinesin family as Kif5C (Kanai et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

et al. 2017

View full text Add to dashboard Cite

Summary Mitochondrial distribution and motility are recognized as central to many cellular functions but their regulation by signaling mechanisms remains to be elucidated. Here we report that ROS, either derived from an extracellular source or intracellularly generated, controls mitochondrial distribution and function, by dose-dependently, specifically and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca2+], mitochondrial membrane potential or permeability transition pore opening, known effectors of oxidative stress. However, multiple lines of genetic and pharmacological evidence support that a ROS-activated MAP kinase, p38α is required for the motility inhibition. Furthermore, anchoring mitochondria directly to kinesins without involvement of the physiological adaptors between the organelles and the motor protein prevents the H2O2–induced decrease in mitochondrial motility. Thus, ROS engage p38α and the motor adaptor complex to exert changes in mitochondrial motility, which likely has both physiological and pathophysiological relevance.

show abstract

Section: Resultsmentioning

confidence: 99%

ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Therefore, all in all, the molecular spectrum of KIF5C related disorders appears to be narrow with a recurrent mutation affecting amino acid Glu237, and with all mutations clustered within the microtubule binding domain of the protein. Mutations of KIF5C have been shown to cause Kinesin proteins to lose their ability to hydrolyze ATP and lead to a non‐functional motor domain (Padzik et al, ). Mutations of the amino acid Glu237 have been shown to affect the binding ability of these microtubule proteins to their targets, protein folding and ATP hydrolysis (Cavallin et al, ; Poirier et al, ).…”

Section: Discussionmentioning

confidence: 99%

Mutations of KIF5C cause a neurodevelopmental disorder of infantile‐onset epilepsy, absent language, and distinctive malformations of cortical development

Michels¹,

Foss

Park³

et al. 2017

American J of Med Genetics Pt A

View full text Add to dashboard Cite

The clinical diagnosis of malformations of cortical development (MCDs) is often challenging due to the complexity of the brain malformation by neuroimaging, the rarity of individual malformation syndromes, and the rapidly evolving genetic landscape of these disorders facilitated with the use of Next Generation Sequencing (NGS) methods. While the clinical and molecular diagnosis of severe cortical malformations, such as classic lissencephaly, is often straightforward, the diagnosis of more subtle and complex types of cortical malformations, such as pachygyria and polymicrogyria (PMG), can be more challenging due to limited knowledge regarding their genetic etiologies. Here, we report two individuals with the same de novo KIF5C mutation who present with subtle malformations of cortical development, early onset epilepsy and significant neurodevelopmental and behavioral issues including absent language. Our data, combined with the limited literature on KIF5C mutations, to date, support that KIF5C mutations are associated with a neurodevelopmental disorder characterized by infantile onset epilepsy, and subtle but recognizable types of brain malformations. We also show that the spectrum of KIF5C mutations is narrow, as five out of the six identified individuals have mutations affecting amino acid Glu237. Therefore, the identification of the clinical and neuroimaging features of this disorder may strongly facilitate rapid and efficient molecular diagnosis.

show abstract

“…Initial single molecule TIRF microscopy observations revealed that KIF1A possesses the novel ability to undergo extensive pausing during a run on taxol-stabilized microtubules ( Figure 1A, Movie S1). While other kinesin motors have been shown to exhibit transient pauses [27,28], the high pause frequency ( Figure 2E, Table 1) of KIF1A has not been previously characterized, compelling us to investigate this behavior further. Additionally, the discovery of this novel pausing behavior led us to redefine our nomenclature of KIF1A motility by dissecting KIF1A motility into three segments ( Figure 1A).…”

Section: Kif1a Exhibits Pausing Behavior and Superprocessive Motilitymentioning

confidence: 96%

Regulation of KIF1A motility via polyglutamylation of tubulin C-terminal tails

Lessard

Zinder

Hotta³

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Axonal transport is a highly regulated cellular process responsible for site-specific neuronal cargo delivery. This process is mediated in part by KIF1A, a member of the kinesin-3 family of molecular motors. It is imperative that KIF1A's highly efficient, superprocessive motility along microtubules is tightly regulated as misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases. However, the regulatory mechanisms responsible for KIF1A's motility, and subsequent proper spatiotemporal cargo delivery, are largely unknown. One potential regulatory mechanism of KIF1A motility is through the posttranslational modifications (PTMs) of axonal microtubules. These PTMs, often occurring on the C-terminal tails of the microtubule tracks, act as molecular "traffic signals" helping to direct kinesin motor cargo delivery. Occurring on neuronal microtubules, C-terminal tail polygutamylation is known to be important for KIF1A cargo transport. KIF1A's initial interaction with microtubule C-terminal tails is facilitated by the K-loop, a positively charged surface loop of the KIF1A motor domain. However, the K-loop's role in KIF1A motility and response to perturbations in C-terminal tail polyglutamylation is underexplored. Using single-molecule imaging, we present evidence of KIF1A's previously unreported pausing behavior on multiple microtubule structures. Further analysis revealed that these pauses link multiple processive segments together, contributing to KIF1A's characteristic superprocessive run length. We further demonstrate that KIF1A pausing is mediated by a Kloop/polyglutamylated C-terminal tail interaction and is a regulatory mechanism of KIF1A motility. In summary, we introduce a new mechanism of KIF1A motility regulation, providing further insight into KIF1A's role in axonal transport.

show abstract

KIF5C S176 Phosphorylation Regulates Microtubule Binding and Transport Efficiency in Mammalian Neurons

Cited by 30 publications

References 46 publications

ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

Mutations of KIF5C cause a neurodevelopmental disorder of infantile‐onset epilepsy, absent language, and distinctive malformations of cortical development

Regulation of KIF1A motility via polyglutamylation of tubulin C-terminal tails

Contact Info

Product

Resources

About