Tohoku University · 생화학·유전·분자생물학
Kyoko Chiba 교수의 연구실은 신경세포 내 축삭 운반을 담당하는 카이네신 모터 단백질의 구조적 기능과 조절 메커니즘을 중심으로 연구를 진행하고 있습니다. 특히 KIF1A, KIF5A, kinesin-1 등 다양한 카이네신 단백질이 뉴런 내에서 시냅스 소포 전구체, APP 등 중요한 세포 소기관을 어떻게 운반하는지에 대한 분자 기전을 해명하고 있으며, 이와 관련된 돌연변이가 신경병증 및 체계성 신경 퇴행성 질환(예: 허브리티리 스파스틱 파리아, ALS)을 유발하는 메커니즘을 규명하고자 합니다. 또한, 축삭 운반의 실시간 관찰을 위한 자동화된 분석 도구 개발(예: KYMOMAKER)을 통해 정량적이고 정밀한 운반 동역학 분석도 함께 수행하고 있습니다.
표시된 성과는 수집된 데이터 기준으로 산출되며, 일부 차이가 있을 수 있습니다.
KIF1A is a kinesin family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules (MTs). In humans, more than 10 point mutations in <i>KIF1A</i> are associated with the motor neuron disease hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus a cogent molecular explanation for how <i>KIF1A</i> mutations lead to neuropathy is not available. In this study, we established in vitro
Kinesin-1 activity is regulated by autoinhibition. Intramolecular interactions within the kinesin heavy chain (KHC) are proposed to be one facet of motor regulation. The KHC also binds to the kinesin light chain (KLC), which has been implicated in both autoinhibition and activation of the motor. We show that the KLC inhibits the kinesin-microtubule interaction independently from the proposed intramolecular interaction within KHC. Cargo-adaptor proteins that bind the KLC stimulated processive mov
Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (∼2.7 μm/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%)
KIF5A is a kinesin superfamily motor protein that transports various cargos in neurons. Mutations in Kif5a cause familial amyotrophic lateral sclerosis (ALS). These ALS mutations are in the intron of Kif5a and induce mis-splicing of KIF5A mRNA, leading to splicing out of exon 27, which in human KIF5A encodes the cargo-binding tail domain of KIF5A. Therefore, it has been suggested that ALS is caused by loss of function of KIF5A. However, the precise mechanisms regarding how mutations in KIF5A cau
Neuronal function depends on axonal transport by kinesin superfamily proteins (KIFs). KIF1A is the molecular motor that transports synaptic vesicle precursors, synaptic vesicles, dense core vesicles and active zone precursors. KIF1A is regulated by an autoinhibitory mechanism; many studies, as well as the crystal structure of KIF1A paralogs, support a model whereby autoinhibited KIF1A is monomeric in solution, whereas activated KIF1A is dimeric on microtubules. KIF1A-associated neurological diso
In tracking analysis, the movement of cargos by motor proteins in axons is often represented by a time-space plot termed a 'kymograph'. Manual creation of kymographs is time-consuming and complicated for cell biologists. Therefore, we developed KYMOMAKER, a simple system that automatically creates a kymograph from a movie without generating multiple time-dissected movie stacks. In addition, KYMOMAKER can automatically extract faint vesicle traces, and can thereby effectively analyze cargos expre
In neurons, amyloid β-protein precursor (APP) is transported by binding to kinesin-1, mediated by JNK-interacting protein 1b (JIP1b), which generates the enhanced fast velocity (EFV) and efficient high frequency (EHF) of APP anterograde transport. Previously, we showed that EFV requires conventional interaction between the JIP1b C-terminal region and the kinesin light chain 1 (KLC1) tetratricopeptide repeat, whereas EHF requires a novel interaction between the central region of JIP1b and the coi
(Cell Reports 39, 110900, May 31, 2022) In the originally published version of this paper, an incorrect definition for the term “MAP7” was introduced during the production process. The correct definition for MAP7 is “microtubule-associated protein 7,” which now appears with the article online. The production team apologizes for the error. Synergistic autoinhibition and activation mechanisms control kinesin-1 motor activityChiba et al.Cell ReportsMay 31, 2022In BriefKinesin-1 (KIF5) transports ca
Abstract Autoinhibition is an important regulatory mechanism for cytoskeletal motor proteins. Kinesin-1 (kinesin hereafter), the ubiquitous plus-end directed microtubule motor, is thought to be controlled by a complicated autoinihibition mechanism, but the molecular details remain unclear. Conformational changes mediated by intramolecular interactions between the C-terminal tail and N-terminal motor domains of the kinesin heavy chain (KHC) are proposed to be one facet of motor regulation. The di
Abstract KIF1A is a kinesin-family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules. In humans, more than ten point mutations in KIF1A are associated with the motor neuron disease, hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus, a clear molecular explanation for how KIF1A mutations lead to neuropathy is not available. In this study, we established in vitro motility
Kinesin-1, a motor protein composed of the kinesin heavy chain (KHC) and the kinesin light chain (KLC), is essential for proper cellular morphogenesis and function. A monoclonal antibody (mAb) called H2 recognizes the KHC in a broad range of species and is one of the most widely used mAbs in cytoskeletal motor research. Here, we present vectors that express recombinant H2 in mammalian cells. We show the recombinant H2 performs as well as the hybridoma-derived H2 in both western blotting and immu
Abstract During prometaphase in mitosis, chromosomes are pushed toward the spindle equator. The chromokinesin Kid, also known as KIF22, moves chromosomes along spindle microtubules during prometaphase. Kid has long been considered as a monomeric and non-processive motor, different from typical kinesins. In this study, we demonstrate that the full-length Kid forms a homodimer and moves processively along microtubules. A conserved coiled-coil domain within the stalk region of Kid is not only capab
Abstract KIF5A is a kinesin superfamily motor protein that transports various cargos in neurons. Mutations in Kif5a cause familial amyotrophic lateral sclerosis (ALS). These ALS mutations are in the intron of Kif5a and induce mis-splicing of KIF5A mRNA, leading to splicing out of exon 27, which in human KIF5A encodes the cargo-binding tail domain of KIF5A. Therefore, it has been suggested that ALS is caused by loss of function of KIF5A. However, the precise mechanisms regarding how mutations in
KIF5Aは細胞内でカーゴ輸送を行うモータータンパク質である．2018年にKIF5Aの遺伝子変異が筋萎縮性側索硬化症（ALS）を引き起こすことが報告された．本稿では最近明らかになってきたALS変異型KIF5Aタンパク質に関する研究結果を紹介する．
