title: DOC2B, C2 domains, and calcium: A tale of intricate interactions.
abstract: Ca(+2)-dependent exocytosis involves vesicle docking, priming, fusion, and recycling. This process is performed and regulated by a vast number of synaptic proteins and depends on proper protein-protein and protein-lipid interactions. Double C2 domain (DOC2) is a protein family of three isoforms found while screening DNA libraries with a C2 probe. DOC2 has three domains: the Munc13-interacting domain and tandem C2s (designated C2A and C2B) connected by a short polar linker. The C2 domain binds phospholipids in a Ca(2+)-dependent manner. This review focuses on the ubiquitously expressed isoform DOC2B. Sequence alignment of the tandem C2 protein family in mouse revealed high homology (81%) between rabphilin-3A and DOC2B proteins. We created a structural model of DOC2B's C2A based on the crystal structure of rabphilin-3A with and without calcium and found that the calcium-binding loops of DOC2B move upon calcium binding, enabling efficient plasma membrane penetration of its C2A. Here, we discuss the potential relation between the DOC2B bioinformatical model and its function and suggest a possible working model for its interaction with other proteins of the exocytotic machinery, including Munc13, Munc18, and syntaxin.
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Friedrich
authors.forename: Adva
authors.initials: A
authors.lastname: Yeheskel
authors.forename: Uri
authors.initials: U
authors.lastname: Ashery
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D051938:Munc18 Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000378:metabolism; D000097624:Rabphilin-3A
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002118:Calcium; D002135:Calcium-Binding Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D033921:Vesicular Transport Proteins; D000097624:Rabphilin-3A; C091524:DOC2A protein, human