title: ZNRF proteins constitute a family of presynaptic E3 ubiquitin ligases.
abstract: Protein ubiquitination has been implicated recently in neural development, plasticity, and degeneration. We previously identified ZNRF1/nin283, a protein with a unique, evolutionarily conserved C-terminal domain containing a juxtaposed zinc finger/RING finger combination. Here we describe the identification of a closely related protein, ZNRF2, thus defining a novel family of ZNRF E3 ubiquitin ligases. Both ZNRF1 and ZNRF2 have E3 ubiquitin ligase activity and are highly expressed in the nervous system, particularly during development. In neurons, ZNRF proteins are located in different compartments within the presynaptic terminal: ZNRF1 is associated with synaptic vesicle membranes, whereas ZNRF2 is present in presynaptic plasma membranes. Mutant ZNRF proteins with a disrupted RING finger, a domain necessary for their E3 function, can each inhibit Ca2+-dependent exocytosis in PC12 cells. These data suggest that ZNRF proteins play a role in the establishment and maintenance of neuronal transmission and plasticity via their ubiquitin ligase activity.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004705:Endocytosis / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D041681:NIH 3T3 Cells; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D017729:Presynaptic Terminals / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000737:chemistry; D009435:Synaptic Transmission / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*
chemical_list: D044767:Ubiquitin-Protein Ligases