Kosower E M
Biophysical Organic Chemistry Unit, School of Chemistry, Sackler Faculty of Exact Sciences, Tel-Aviv University, Ramat-Aviv, Israel.
Prog Clin Biol Res. 1989;289:279-92.
Folding of the five polypeptide subunits (alpha 2 beta gamma delta) of the nicotinic acetylcholine receptor (AChR) into a functional structural model is described. The principles used to arrange the sequences into a structure include: (1) Hydrophobicity----membrane crossing segments (2) amphipathic character----ion-carrying segments (ion channel with single group rotations) (3) molecular shape (elongated, pentagonal cylinder)----folding dimensions of exobilayer portion (4) choice of acetylcholine binding sites----specific folding of exobilayer segments (5) location of reducible disulfides (near agonist binding site)----additional specification of exobilayer arrangement (6) genetic homology----consistency of functional group choices (7) noncompetitive antagonist labeling----arrangement of bilayer helices. The AChR model is divided into three parts (a) exobilayer: 11 antiparallel beta-strands from each subunit (b) bilayer: 4 hydrophobic and 1 amphiphilic alpha-helices from each subunit and (c) cytoplasmic: one (folded) loop from each subunit. The exobilayer strands can form a closed "flower" (the "resting state") which is opened ("activated") by agonists bound perpendicular to the strands. Rearrangement of the agonists to a strand-parallel position and partial closing of the "flower" leads to a desensitized receptor. The actions of acetylcholine and succinoyl and suberoyl bis-cholines are clarified by the model. The opening and closing of the exobilayer "flower" controls access to the ion channel which is composed of the 5 amphiphilic bilayer helices. A molecular mechanism for ion flow in the channel is given. The unusual photolabeling of intrabilayer serines in alpha, beta and delta, but not in gamma-subunits near the binding site for non-competitive antagonists (NCAs) is explained. The dynamic behavior of the AChR channel and many experimental results can be interpreted in terms of the model.
描述了烟碱型乙酰胆碱受体（AChR）的五个多肽亚基（α2βγδ）折叠成功能结构模型的过程。用于将序列排列成结构的原则包括：（1）疏水性——跨膜片段；（2）两亲性特征——离子携带片段（具有单组旋转的离子通道）；（3）分子形状（细长的五角柱体）——外膜层部分的折叠尺寸；（4）乙酰胆碱结合位点的选择——外膜层片段的特定折叠；（5）可还原二硫键的位置（靠近激动剂结合位点）——外膜层排列的额外规范；（6）基因同源性——功能基团选择的一致性；（7）非竞争性拮抗剂标记——双层螺旋的排列。AChR模型分为三个部分：（a）外膜层：每个亚基有11条反平行β链；（b）双层：每个亚基有4条疏水α螺旋和1条两亲性α螺旋；（c）细胞质：每个亚基有一个（折叠的）环。外膜层链可形成一个封闭的“花”（“静息状态”），与链垂直结合的激动剂可使其打开（“激活”）。激动剂重新排列到与链平行的位置并使“花”部分关闭会导致受体脱敏。该模型阐明了乙酰胆碱以及琥珀酰胆碱和辛二酰胆碱的作用。外膜层“花”的打开和关闭控制着由5条两亲性双层螺旋组成的离子通道的通路。给出了通道中离子流动的分子机制。解释了在α、β和δ亚基中，而非在靠近非竞争性拮抗剂（NCA）结合位点的γ亚基中，双层内丝氨酸的异常光标记现象。AChR通道的动态行为以及许多实验结果都可以根据该模型进行解释。
