Functional Differences Between Neuronal and Non-neuronal Isoforms of Drebrin

Actin cytoskeleton is vital for neuronal function. Drebrin is a key F-actin binding protein in neurons which is linked to the filaments' stabilization. As mammalian brain develops, drebrin expression pattern switches from non-neuronal (drebrin E, Embryonic) to neuron-specific isoform (drebrin A, Adult), but the evolutionary need for such a switch is enigmatic. Prior in cellulo and in vivo work suggested a non-redundant role of drebrin isoforms in neuronal development and function, however, molecular level understanding of it is lacking. Here we used mutagenesis, bulk solution assays, and time-lapse TIRF microscopy to probe for functional differences between drebrin isoforms. We found that drebrin A and E are functionally distinct and differ in their ability to inhibit F-actin depolymerization. We showed that both isoforms act as permissive cappers of the barbed end of actin, however, drebrin A has a significantly stronger capping activity, compared to that of the non-neuronal drebrin E. Probing for the molecular level insights on the observed differences revealed that the adult-specific exon in neuronal drebrin A contains an actin binding interface which enhances its permissive capping activity. Strikingly, F-actin decoration by neuronal drebrin A confers significantly stronger resistance to cofilin-mediated severing compared to that of drebrin E. Our results provide novel molecular level insights on functional differences between drebrin isoforms, which deepen our understanding of cytoskeletal regulation in the neuronal context. Our results also helps interpreting the previously reported data related to the silencing or knockout of the neuronal drebrin isoform.