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Eugene A Katrukha - One of the best experts on this subject based on the ideXlab platform.
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structural basis for misregulation of kinesin kif21a autoinhibition by cfeom1 disease mutations
Scientific Reports, 2016Co-Authors: Sarah Bianchi, Rolf Jaussi, John H Missimer, Wilhelmina E. Van Riel, Natacha Olieric, Daniel Frey, Sebastian H W Kraatz, Ilya Grigoriev, Eugene A Katrukha, Vincent OliericAbstract:Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
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structural basis for misregulation of kinesin kif21a autoinhibition by cfeom1 disease mutations
Scientific Reports, 2016Co-Authors: Sarah Bianchi, Rolf Jaussi, John H Missimer, Wilhelmina E. Van Riel, Natacha Olieric, Daniel Frey, Sebastian H W Kraatz, Ilya Grigoriev, Eugene A Katrukha, Vincent OliericAbstract:Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
Nobutaka Hirokawa - One of the best experts on this subject based on the ideXlab platform.
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KIF2A regulates the development of dentate granule cells and postnatal hippocampal wiring
eLife, 2018Co-Authors: Noriko Homma, Ruyun Zhou, Muhammad Imran Naseer, Adeel G Chaudhary, Mohammed H Alqahtani, Nobutaka HirokawaAbstract:Kinesin super family protein 2A (KIF2A), an ATP-dependent microtubule (MT) destabilizer, regulates cell migration, axon elongation, and pruning in the developing nervous system. KIF2A mutations have recently been identified in patients with malformed cortical development. However, postnatal KIF2A is continuously expressed in the hippocampus, in which new neurons are generated throughout an individual's life in established neuronal circuits. In this study, we investigated KIF2A function in the postnatal hippocampus by using tamoxifen-inducible KIF2A conditional knockout (KIF2A-cKO) mice. Despite exhibiting no significant defects in neuronal proliferation or migration, KIF2A-cKO mice showed signs of an epileptic hippocampus. In addition to mossy fiber sprouting, the KIF2A-cKO dentate granule cells (DGCs) showed dendro-axonal conversion, leading to the growth of many aberrant overextended dendrites that eventually developed axonal properties. These results suggested that postnatal KIF2A is a key length regulator of DGC developing neurites and is involved in the establishment of precise postnatal hippocampal wiring.
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the molecular motor kif1a transports the trka neurotrophin receptor and is essential for sensory neuron survival and function
Neuron, 2016Co-Authors: Yosuke Tanaka, Shinsuke Niwa, Atena Farkhondeh, Ruyun Zhou, Ming Dong, Nobutaka Hirokawa, Li WangAbstract:Summary KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a +/− dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a +/− neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a +/− DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the pain receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway.
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Microtubule Destabilizer KIF2A Undergoes Distinct Site-Specific Phosphorylation Cascades that Differentially Affect Neuronal Morphogenesis.
Cell reports, 2015Co-Authors: Tadayuki Ogawa, Nobutaka HirokawaAbstract:Neurons exhibit dynamic structural changes in response to extracellular stimuli. Microtubules (MTs) provide rapid and dramatic cytoskeletal changes within the structural framework. However, the molecular mechanisms and signaling networks underlying MT dynamics remain unknown. Here, we have applied a comprehensive and quantitative phospho-analysis of the MT destabilizer KIF2A to elucidate the regulatory mechanisms of MT dynamics within neurons in response to extracellular signals. Interestingly, we identified two different sets of KIF2A phosphorylation profiles that accelerate (A-type) and brake (B-type) the MT depolymerization activity of KIF2A. Brain-derived neurotrophic factor (BDNF) stimulates PAK1 and CDK5 kinases, which decrease the MT depolymerizing activity of KIF2A through B-type phosphorylation, resulting in enhanced outgrowth of neural processes. In contrast, lysophosphatidic acid (LPA) induces ROCK2 kinase, which suppresses neurite outgrowth from round cells via A-type phosphorylation. We propose that these two mutually exclusive forms of KIF2A phosphorylation differentially regulate neuronal morphogenesis during development.
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molecular motor kif5a is essential for gabaa receptor transport and kif5a deletion causes epilepsy
Neuron, 2012Co-Authors: Kazuo Nakajima, Noriko Homma, Dae-hyun Seog, Yosuke Takei, Nobutaka HirokawaAbstract:Summary KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a -knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABA A receptor (GABA A R)-mediated synaptic transmission. We also identified reduced cell surface expression of GABA A R in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABA A R-associated protein (GABARAP) that is known to be involved in GABA A R trafficking. KIF5A regulated neuronal surface expression of GABA A Rs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission.
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phosphatidylinositol 4 phosphate 5 kinase alpha pipkα regulates neuronal microtubule depolymerase kinesin KIF2A and suppresses elongation of axon branches
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Yasuko Noda, Noriko Homma, Shinsuke Niwa, Hiroyuki Fukuda, Shinobu Imajoohmi, Nobutaka HirokawaAbstract:Neuronal morphology is regulated by cytoskeletons. Kinesin superfamily protein 2A (KIF2A) depolymerizes microtubules (MTs) at growth cones and regulates axon pathfinding. The factors controlling KIF2A in neurite development remain totally elusive. Here, using immunoprecipitation with an antibody specific to KIF2A, we identified phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKα) as a candidate membrane protein that regulates the activity of KIF2A. Yeast two-hybrid and biochemical assays demonstrated direct binding between KIF2A and PIPKα. Partial colocalization of the clusters of punctate signals for these two molecules was detected by confocal microscopy and photoactivated localization microscopy. Additionally, the MT-depolymerizing activity of KIF2A was enhanced in the presence of PIPKα in vitro and in vivo. PIPKα suppressed the elongation of axon branches in a KIF2A-dependent manner, suggesting a unique PIPK-mediated mechanism controlling MT dynamics in neuronal development.
Samantha A Spangler - One of the best experts on this subject based on the ideXlab platform.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
Wilhelmina E. Van Riel - One of the best experts on this subject based on the ideXlab platform.
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structural basis for misregulation of kinesin kif21a autoinhibition by cfeom1 disease mutations
Scientific Reports, 2016Co-Authors: Sarah Bianchi, Rolf Jaussi, John H Missimer, Wilhelmina E. Van Riel, Natacha Olieric, Daniel Frey, Sebastian H W Kraatz, Ilya Grigoriev, Eugene A Katrukha, Vincent OliericAbstract:Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
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structural basis for misregulation of kinesin kif21a autoinhibition by cfeom1 disease mutations
Scientific Reports, 2016Co-Authors: Sarah Bianchi, Rolf Jaussi, John H Missimer, Wilhelmina E. Van Riel, Natacha Olieric, Daniel Frey, Sebastian H W Kraatz, Ilya Grigoriev, Eugene A Katrukha, Vincent OliericAbstract:Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
Ilya Grigoriev - One of the best experts on this subject based on the ideXlab platform.
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structural basis for misregulation of kinesin kif21a autoinhibition by cfeom1 disease mutations
Scientific Reports, 2016Co-Authors: Sarah Bianchi, Rolf Jaussi, John H Missimer, Wilhelmina E. Van Riel, Natacha Olieric, Daniel Frey, Sebastian H W Kraatz, Ilya Grigoriev, Eugene A Katrukha, Vincent OliericAbstract:Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
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structural basis for misregulation of kinesin kif21a autoinhibition by cfeom1 disease mutations
Scientific Reports, 2016Co-Authors: Sarah Bianchi, Rolf Jaussi, John H Missimer, Wilhelmina E. Van Riel, Natacha Olieric, Daniel Frey, Sebastian H W Kraatz, Ilya Grigoriev, Eugene A Katrukha, Vincent OliericAbstract:Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
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cfeom1 associated kinesin kif21a is a cortical microtubule growth inhibitor
Developmental Cell, 2013Co-Authors: Babet Van Der Vaart, Josta T Kevenaar, Benjamin P Bouchet, Wilhelmina E. Van Riel, Laura F Gumy, Ilya Grigoriev, Harinath Doodhi, Eugene A Katrukha, Samantha A SpanglerAbstract:Summary Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
