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Structural insight into the mechanism of synergistic autoinhibition of SAD kinases
Jing-Xiang Wu,Yun-Sheng Cheng,Jue Wang,Lei Chen,Mei Ding & Jia-Wei Wu
NATURE COMMUNICATIONS
Abstract
The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an ‘αC-out’ inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases.
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DOI:10.1038/ncomms9953 |
论文题目: |
Structural insight into the mechanism of synergistic autoinhibition of SAD kinases |
英文论文题目: |
Structural insight into the mechanism of synergistic autoinhibition of SAD kinases |
第一作者: |
Jing-Xiang Wu,Yun-Sheng Cheng,Jue Wang,Lei Chen,Mei Ding & Jia-Wei Wu |
英文第一作者: |
Jing-Xiang Wu,Yun-Sheng Cheng,Jue Wang,Lei Chen,Mei Ding & Jia-Wei Wu |
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2015-12-07 |
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The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an ‘αC-out’ inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases. |
英文摘要: |
The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an ‘αC-out’ inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases. |
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NATURE COMMUNICATIONS |
英文刊物名称: |
NATURE COMMUNICATIONS |
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Jing-Xiang Wu,Yun-Sheng Cheng,Jue Wang,Lei Chen,Mei Ding & Jia-Wei Wu. Structural insight into the mechanism of synergistic autoinhibition of SAD kinases. NATURE COMMUNICATIONS. DOI:10.1038/ncomms9953 |
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