title: Drebrin contains a cryptic F-actin-bundling activity regulated by Cdk5 phosphorylation.
abstract: 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.
authors: Medical Research Council MRC Centre for Developmental Neurobiology, King's College London, London SE1 1UL, England, UK.
authors: Daniel C
authors: DC
authors: Worth
authors: Catherine N
authors: CN
authors: Daly
authors: Sara
authors: S
authors: Geraldo
authors: Fazal
authors: F
authors: Oozeer
authors: Phillip R
authors: PR
authors: Gordon-Weeks
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D055495:Neurogenesis; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D022502:Stress Fibers / Q000378:metabolism / Q000648:ultrastructure; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D050505:Mutant Proteins; D009479:Neuropeptides; C053386:drebrins; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5
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