14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice
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- Yokoi, Norihiko
- Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
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- Fukata, Yuko
- Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
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- Okatsu, Kei
- Department of Chemistry, Graduate School of Science, Kyoto University
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- Yamagata, Atsushi
- RIKEN Center for Biosystems Dynamics Research
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- Liu, Yan
- Department of Chemistry, Graduate School of Science, Kyoto University
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- Sanbo, Makoto
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences
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- Miyazaki, Yuri
- Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
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- Goto, Teppei
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences
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- Abe, Manabu
- Department of Animal Model Development, Brain Research Institute, Niigata University
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- Kassai, Hidetoshi
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
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- Sakimura, Kenji
- Department of Animal Model Development, Brain Research Institute, Niigata University
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- Meijer, Dies
- Centre for Discovery Brain Sciences, University of Edinburgh
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- Hirabayashi, Masumi
- Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies); Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences
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- Fukai, Shuya
- Department of Chemistry, Graduate School of Science, Kyoto University
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- Fukata, Masaki
- Division of Membrane Physiology, Department of Molecular and Cellular Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences; Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies)
Abstract
What percentage of the protein function is required to prevent disease symptoms is a fundamental question in genetic disorders. Decreased transsynaptic LGI1-ADAM22 protein complexes, because of their mutations or autoantibodies, cause epilepsy and amnesia. However, it remains unclear how LGI1-ADAM22 levels are regulated and how much LGI1-ADAM22 function is required. Here, by genetic and structural analysis, we demonstrate that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3. This interaction protects LGI1-ADAM22 from endocytosis-dependent degradation. Accordingly, forskolin-induced PKA activation increases ADAM22 levels. Leveraging a series of ADAM22 and LGI1 hypomorphic mice, we find that ∼50% of LGI1 and ∼10% of ADAM22 levels are sufficient to prevent lethal epilepsy. Furthermore, ADAM22 function is required in excitatory and inhibitory neurons. These results suggest strategies to increase LGI1-ADAM22 complexes over the required levels by targeting PKA or 14-3-3 for epilepsy treatment.
Journal
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- Cell Reports
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Cell Reports 37 (11), 110107-, 2021-12
Elsevier BV
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Keywords
Details
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- CRID
- 1050008998069335552
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- NII Article ID
- 120007177780
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- ISSN
- 22111247
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- HANDLE
- 2433/266603
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- Text Lang
- en
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- Article Type
- journal article
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- Data Source
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- IRDB
- Crossref
- CiNii Articles
- KAKEN
