Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity
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Kinesin motor proteins play a fundamental role for normal neuronal development by controlling intracellular cargo transport and microtubule (MT) cytoskeleton organization. Regulating kinesin activity is important to ensure their proper functioning, and their misregulation often leads to severe human neurological disorders. Homozygous nonsense mutations in kinesin-binding protein (KBP)/KIAA1279 cause the neurological disorder Goldberg-Shprintzen syndrome (GOSHS), which is characterized by intellectual disability, microcephaly, and axonal neuropathy. Here, we show that KBP regulates kinesin activity by interacting with the motor domains of a specific subset of kinesins to prevent their association with the MT cytoskeleton. The KBP-interacting kinesins include cargo-transporting motors such as kinesin-3/KIF1A and MT-depolymerizing motor kinesin-8/KIF18A. We found that KBP blocks KIF1A/UNC-104-mediated synaptic vesicle transport in cultured hippocampal neurons and in C. elegans PVD sensory neurons. In contrast, depletion of KBP results in the accumulation of KIF1A motors and synaptic vesicles in the axonal growth cone. We also show that KBP regulates neuronal MT dynamics by controlling KIF18A activity. Our data suggest that KBP functions as a kinesin inhibitor that modulates MT-based cargo motility and depolymerizing activity of a subset of kinesin motors. We propose that misregulation of KBP-controlled kinesin motors may represent the underlying molecular mechanism that contributes to the neuropathological defects observed in GOSHS patients.
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KIF15, an interactor of KIF18A, might have been under positive selection in modern humans and contains two HHMCs.
“an interactor of KIF18A, KIF1597, might have been under positive selection in modern humans33, and contains two HHMCs.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [97]
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- Authors
- Kevenaar, J. T., Bianchi, S., van Spronsen, M., Olieric, N., Lipka, J., Frias, C. P., Mikhaylova, M., Harterink, M., Keijzer, N., Wulf, P. S., Hilbert, M., Kapitein, L. C., de Graaff, E., Ahkmanova, A., Steinmetz, M. O., & Hoogenraad, C. C.
- Affiliations
- Utrecht University (NL)
- Paul Scherrer Institute (CH)
- Erasmus MC (NL)
- Corresponding author
- Hoogenraad, Casper C.
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 26
- Issue
- 7
- Pages
- 849-861
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2290358349
- Cited by
- 110
- References
- 45
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 8 · 2021: 17 · 2020: 15 · 2019: 14 · 2018: 7 · 2017: 12 · 2016: 5
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Science Foundation
- European Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (138659)
- ZonMw
- Erasmus Medisch Centrum
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- kinesin-3, KIF1A, kinesin-8, KIF18A, microtubule dynamics, cargo trafficking, synaptic vesicle transport, axonal growth cones, neuronal cytoskeleton, axonal neuropathy, nonsense mutation, intellectual disability, microcephaly
- MeSH terms
- Animals, Carrier Proteins, Hirschsprung Disease, Microtubules, Nerve Tissue Proteins, Neurons, Synaptic Vesicles, Kinesins, Caenorhabditis elegans, Craniofacial Abnormalities, Mice
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