期刊
JOURNAL OF CELL BIOLOGY
卷 202, 期 5, 页码 793-806出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201303005
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资金
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Wellcome Trust
- Research into Aging
- Fundacao para a Ciencia e Tecnologia, Portugal
- BBSRC [BB/H010963/1] Funding Source: UKRI
- MRC [G0901899] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H010963/1] Funding Source: researchfish
- Medical Research Council [G0901899] Funding Source: researchfish
Drebrin is an actin filament (F-actin)-binding protein with crucial roles in neuritogenesis and synaptic plasticity. Drebrin couples dynamic microtubules to F-actin in growth cone filopodia via binding to the microtubule-binding +TIP protein EB3 and organizes F-actin in dendritic spines. Precisely how drebrin interacts with F-actin and how this is regulated is unknown. We used cellular and in vitro assays with a library of drebrin deletion constructs to map F-actin binding sites. We discovered two domains in the N-terminal half of drebrin a coiled-coil domain and a helical domain that independently bound to F-actin and cooperatively bundled F-actin. However, this activity was repressed by an intramolecular interaction relieved by Cdk5 phosphorylation of serine 142 located in the coiled-coil domain. Phospho-mimetic and phospho-dead mutants of serine 142 interfered with neuritogenesis and coupling of microtubules to F-actin in growth cone filopodia. These findings show that drebrin contains a cryptic F-actin-bundling activity regulated by phosphorylation and provide a mechanistic model for microtubule-F-actin coupling.
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