Structural Basis of Arc Binding to Synaptic Proteins [electronic resource] : Implications for Cognitive Disease

• Ngôn ngữ: eng
• Ký hiệu phân loại: 612. Human physiology
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 490-500 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261186
• Chủ đề: 1. 59 basic biological sciences; 2. 60 applied life sciences

Tóm tắt

Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. Here we report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was ?domesticated? in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARP?2 (Stargazin) and CaMKII peptides and is essential for Arc?s synaptic function. A consensus sequence for Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc?s synaptic action may be druggable. Finally, these studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc?s contribution to neural plasticity and disease.