Molecular modeling and mutagenesis of gap junction channels

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• 作者：Julio A. Kovacs ; Kent A. Baker ; Guillermo A. Altenberg ; Ruben Abagyan ; Mark Yeager
• 关键词：Gap junction channel ; Connexon ; Intercellular communication ; Electron microscopy ; Mutagenesis ; Computational modeling
• 刊名：Progress in Biophysics and Molecular Biology
• 出版年：2007
• 期刊代码：131_00796107
• 类别：bio
• 出版时间：May-June 2007
• 卷：94
• 期：1-2
• 页码：15-28
• 文件大小：1584 K

摘要

Gap junction channels connect the cytoplasms of adjacent cells through the end-to-end docking of hexameric hemichannels called connexons. Each connexon is formed by a ring of 24 α-helices that are staggered by 30° with respect to those in the apposed connexon. Current evidence suggests that the two connexons are docked by interdigitated, anti-parallel β strands across the extracellular gap. The second extracellular loop, E2, guides selectivity in docking between connexons formed by different isoforms. There is considerably more sequence variability of the N-terminal portion of E2, suggesting that this region dictates connexon coupling. Mutagenesis, biochemical, dye-transfer and electrophysiological data, combined with computational studies, have suggested possible assignments for the four transmembrane α-helices within each subunit. Most current models assign M3 as the major pore-lining helix. Mapping of human mutations onto a C^α model suggested that native helix packing is important for the formation of fully functional channels. Nevertheless, a mutant in which the M4 helix has been replaced with polyalanine is functional, suggesting that M4 is located on the perimeter of the channel. In spite of this substantial progress in understanding the structural biology of gap junction channels, an experimentally determined structure at atomic resolution will be essential to confirm these concepts.