Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors

被引:82
作者
Taly, Antoine
Corringer, Pierre-Jean
Grutter, Thomas
de Carvalho, Lia Prado
Karplus, Martin
Changeux, Jean-Pierre
机构
[1] Univ Louis Pasteur Strasbourg 1, Lab Chim Biophys, Inst Sci Ingn Supermol, F-67083 Strasbourg, France
[2] Inst Pasteur, CNRS, Unite Rech Associee, F-75724 Paris 15, France
[3] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA
关键词
allosteric transition; nicotinic receptor; pathological mutations; normal mode perturbation scanning;
D O I
10.1073/pnas.0607477103
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
Nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated ion channels composed of subunits that consist of an extracellular domain that carries the ligand-binding site and a distinct ion-pore domain. Signal transduction results from the allosteric coupling between the two domains: the distance from the binding site to the gate of the pore domain is 50 A. Normal mode analysis with a C. Gaussian network of a new structural model of the neuronal alpha 7 nAChR showed that the lowest mode involves a global quaternary twist motion that opens the ion pore. A molecular probe analysis, in which the network is modified at each individual amino acid residue, demonstrated that the major effect is to change the frequency, but not the form, of the twist mode. The largest effects were observed for the ligand-binding site and the Cys-loop. Most (24/27) of spontaneous mutations known to cause congenital myasthenia and autosomal dominant nocturnal frontal lobe epilepsy are located either at the interface between subunits or, within a given subunit, at the interface between rigid blocks. These interfaces are modified significantly by the twist mode. The present analysis, thus, supports the quaternary twist model of the nAChR allosteric transition and provides a qualitative interpretation of the effect of the mutations responsible for several receptor pathologies.
引用
收藏
页码:16965 / 16970
页数:6
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