![]() ![]() Syndapin 1 is composed of an N-terminal F-BAR linked to a C-terminal dynamin-binding SH3 domain via a long flexible tether containing NPF motifs ( Fig. Similar regulatory mechanisms must operate to control the membrane-deforming activities of other BAR domain proteins ( 19– 21) and the consumption of membrane buds and tubules by dynamin-mediated fission ( 9, 12, 17). The role of syndapin in SV recycling appears to be under tight regulatory control by stimulation-induced dephosphorylation of dynamin 1 in nerve terminals ( 14). Similar effects are observed upon perturbation of syndapin function in lamprey reticulospinal axons ( 18). Knockdown of syndapin 1 causes impaired axon development and branching and leads to defects in bulk endocytosis of synaptic vesicle (SV) membranes under intense stimulation in primary neurons ( 17). The F-BAR and SH3 domains of syndapins are connected via a flexible linker containing NPF motifs that interact with EH domain proteins, most notably EHD1 ( 3, 13, 15). Syndapins are synaptically enriched proteins of the Fer-CIP4 homology-BAR (F-BAR) subfamily of BAR domain proteins that via their SH3 domain bind to dynamin ( 14) and to actin regulatory proteins such as N-WASP ( 15) and cordon bleu (COBL) ( 16). How precisely membrane deformation by BAR domain proteins is regulated at the cellular level and how this may be coupled to fission are largely unknown. Frequently, BAR domain proteins, such as syndapin, sorting nexin 9 ( 8), endophilin, and amphiphysin ( 9), also contain an SH3 domain that serves as an interaction platform for proline-rich motif-containing proteins including the large membrane-fissioning GTPase dynamin ( 10), suggesting that membrane bending is intimately linked with GTP-hydrolysis-dependent vesicle or tubule fission ( 9, 11, 12). Self-assembly of BAR domain proteins, often in combination with the presence of amphipathic helices ( 6, 7), may then induce or stabilize membrane curvature de novo. BAR domains are characterized by α-helical coiled coils that dimerize into modules with a positively charged surface that interacts with phospholipid membranes ( 4, 5). In most cases, dynamic membrane remodeling is accomplished by the reversible assembly of membrane-deforming proteins ( 1, 2), most notably by members of the Bin/amphiphysin/Rvs (BAR) domain superfamily ( 3). Our data thus suggest a structure-based model for SH3-mediated regulation of BAR/F-BAR domain function.Įukaryotic cells are characterized by a diverse array of membranous structures including vesicles, tubules, and pleiomorphic vacuoles that enable cellular processes such as organelle biogenesis, cell division, cell migration, secretion, and endocytosis. We hypothesize that this mechanism might be commonly used to regulate BAR/F-BAR domain-induced membrane deformation and to potentially couple this process to dynamin-mediated fission. ![]() Release from the clamped conformation is driven by association of syndapin 1 SH3 with the proline-rich domain of dynamin 1, thereby unlocking its potent membrane-bending activity. Our data show that syndapin 1 F-BAR-mediated membrane deformation is subject to autoinhibition by its SH3 domain. Here we present the crystal structures of full-length syndapin 1 and its F-BAR domain. How precisely BAR/F-BAR domain-mediated membrane deformation is regulated at the cellular level is unknown. BAR/F-BAR domain proteins often contain an SH3 domain, which recruits binding partners such as the oligomeric membrane-fissioning GTPase dynamin. Membrane curvature induction and stabilization are encoded within the BAR or Fer-CIP4 homology-BAR (F-BAR) domains, α-helical coiled coils that dimerize into membrane-binding modules. ![]() Members of the Bin/amphiphysin/Rvs (BAR) domain protein superfamily are involved in membrane remodeling in various cellular pathways ranging from endocytic vesicle and T-tubule formation to cell migration and neuromorphogenesis. ![]()
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