Zn2+ interaction with Alzheimer amyloid beta protein calcium channels

被引:219
作者
Arispe, N
Pollard, HB
Rojas, E
机构
[1] Lab. of Cell Biology and Genetics, Natl. Inst. Diabet., Digest. K., National Institutes of Health, Bethesda
关键词
giant amyloid beta-protein channel; lipid bilayer; zinc-binding motif; zinc blockade;
D O I
10.1073/pnas.93.4.1710
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The Alzheimer disease 40-residue amyloid beta protein (A beta P[1-40]) forms cation-selective channels across acidic phospholipid bilayer membranes with spontaneous transitions over a wide range of conductances ranging from 40 to 4000 pS. Zn2+ has been reported to bind to A beta P[1-40] with high affinity, and it has been implicated in the formation of amyloid plaques, We now report the functional consequences of such Zn2+ binding for the A beta P[1-40] channel. Provided the A beta P[1-40] channel is expressed in the low conductance (<400 pS) mode, Zn2+ blocks the open channel in a dose-dependent manner, For A beta P[1-40] channels in the giant conductance mode (>400 pS), Zn2+ doses in the millimolar range were required to exert substantial blockade. The Zn2+ chelator o-phenanthroline reverses the blockade. We also found that Zn2+ modulates A beta P[1-40] channel gating and conductance only from one side of the channel, These data are consistent with predictions of our recent molecular modeling studies on A beta P[1-40] channels indicating asymmetric Zn2+-A beta P[1-40] interactions at the entrance to the pore.
引用
收藏
页码:1710 / 1715
页数:6
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