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Nature:钾(K+)通道的控制机制

来源:未知 编辑:admin 发布时间:2017-08-14
Nature:钾(K+)通道的控制机制

在K+离子通道打开之后,当这种通道的一个细胞质部分进入一个能以物理方式阻止离子穿过通道小孔来渗透的位置时,它们便会频繁地“失活”(inactivate)。这项研究表明,由Ca2+激活的BK通道的一个离子通道亚单元的一个特定的、内在发生紊乱的肽区域,会通过立体选择性结合产生其功能性影响。BK 3a辅助亚单元肽,只有当它是由L-氨基酸而不是D-氨基酸组成时,才会使与其相关的BK通道失活。这意味着,“两步失活过程”要求,如果要辅助亚单元去阻断该通道的话,那么一个立体选择性结合事件(而不仅仅是小孔的空间阻断)就必需要出现。

Nature 485 (7396) | doi:10.1038/nature10994

发表日期:12年5月3日

原文摘要:

Stereospecific binding of a disordered peptide segment mediates BK channel inactivation

A number of functionally important actions of proteins are mediated by short, intrinsically disordered peptide segments1, but the molecular interactions that allow disordered domains to mediate their effects remain a topic of active investigation2, 3, 4, 5. Many K+ channel proteins, after initial channel opening, show a time-dependent reduction in current flux, termed ‘inactivation’, which involves movement of mobile cytosolic peptide segments (approximately 20–30 residues) into a position that physically occludes ion permeation6, 7, 8. Peptide segments that produce inactivation show little amino-acid identity6, 9, 10, 11, 12, 13 and tolerate appreciable mutational substitutions13 without disrupting the inactivation process. Solution nuclear magnetic resonance of several isolated inactivation domains reveals substantial conformational heteroGENEity with only minimal tendency to ordered structures14, 15, 16, 17. Channel inactivation mechanisms may therefore help us to decipher how intrinsically disordered regions mediate functional effects. Whereas many aspects of inactivation of voltage-dependent K+ channels (Kv) can be described by a simple one-step occlusion mechanism6, 7, 18, 19, inactivation of the voltage-dependent large-conductance Ca2+-gated K+ (BK) channel mediated by peptide segments of auxiliary β-subunits involves two distinguishable kinetic steps20, 21. Here we show that two-step inactivation mediated by an intrinsically disordered BK β-subunit peptide involves a stereospecific binding interaction that precedes blockade. In contrast, blocking mediated by a Shaker Kv inactivation peptide is consistent with direct, simple occlusion by a hydrophobic segment without substantial steric requirement. The results indicate that two distinct types of molecular interaction between disordered peptide segments and their binding sites produce qualitatively similar functions.

作者:青岚 点击:

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