Coles M, Bicknell W, Watson A A, Fairlie D P, Craik D J
Centre for Drug Design and Development, The University of Queensland, Brisbane, Australia.
Biochemistry. 1998 Aug 4;37(31):11064-77. doi: 10.1021/bi972979f.
The three-dimensional solution structure of the 40 residue amyloid beta-peptide, Abeta(1-40), has been determined using NMR spectroscopy at pH 5.1, in aqueous sodium dodecyl sulfate (SDS) micelles. In this environment, which simulates to some extent a water-membrane medium, the peptide is unstructured between residues 1 and 14 which are mainly polar and likely solvated by water. However, the rest of the protein adopts an alpha-helical conformation between residues 15 and 36 with a kink or hinge at 25-27. This largely hydrophobic region is likely solvated by SDS. Based on the derived structures, evidence is provided in support of a possible new location for the transmembrane domain of Abeta within the amyloid precursor protein (APP). Studies between pH 4.2 and 7.9 reveal a pH-dependent helix-coil conformational switch. At the lower pH values, where the carboxylate residues are protonated, the helix is uncharged, intact, and lipid-soluble. As the pH increases above 6. 0, part of the helical region (15-24) becomes less structured, particularly near residues E22 and D23 where deprotonation appears to facilitate unwinding of the helix. This pH-dependent unfolding to a random coil conformation precedes any tendency of this peptide to aggregate to a beta-sheet as the pH increases. The structural biology described herein for Abeta(1-40) suggests that (i) the C-terminal two-thirds of the peptide is an alpha-helix in membrane-like environments, (ii) deprotonation of two acidic amino acids in the helix promotes a helix-coil conformational transition that precedes aggregation, (iii) a mobile hinge exists in the helical region of Abeta(1-40) and this may be relevant to its membrane-inserting properties and conformational rearrangements, and (iv) the location of the transmembrane domain of amyloid precursor proteins may be different from that accepted in the literature. These results may provide new insight to the structural properties of amyloid beta-peptides of relevance to Alzheimer's disease.
已通过核磁共振光谱法在pH 5.1的十二烷基硫酸钠（SDS）水胶束中测定了40个残基的β淀粉样肽Abeta(1 - 40)的三维溶液结构。在这种在一定程度上模拟水 - 膜介质的环境中，该肽在残基1和14之间无结构，这些残基主要是极性的，可能被水溶剂化。然而，蛋白质的其余部分在残基15和36之间采用α - 螺旋构象，在25 - 27处有一个扭结或铰链。这个主要为疏水的区域可能被SDS溶剂化。基于推导的结构，提供了证据支持Abeta跨膜结构域在淀粉样前体蛋白（APP）内可能的新位置。在pH 4.2至7.9之间的研究揭示了一种pH依赖性的螺旋 - 卷曲构象转换。在较低的pH值下，羧酸根残基质子化，螺旋不带电荷、完整且脂溶性。当pH值增加到6.0以上时，螺旋区域（15 - 24）的一部分变得结构较少，特别是在残基E22和D23附近，去质子化似乎促进了螺旋的解旋。随着pH值升高，这种pH依赖性的向无规卷曲构象的展开先于该肽聚集形成β - 折叠的任何趋势。本文所述的Abeta(1 - 40)的结构生物学表明：（i）该肽的C末端三分之二在类似膜的环境中是α - 螺旋；（ii）螺旋中两个酸性氨基酸的去质子化促进了在聚集之前的螺旋 - 卷曲构象转变；（iii）Abeta(1 - 40)的螺旋区域存在一个可移动的铰链，这可能与其膜插入特性和构象重排有关；（iv）淀粉样前体蛋白跨膜结构域的位置可能与文献中公认的不同。这些结果可能为与阿尔茨海默病相关的β淀粉样肽的结构特性提供新的见解。
