Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors
Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors
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DOI：
10.1021/bi992580m
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发表时间：
2000-03-14
期刊：
影响因子：
2.9
通讯作者：
Nicholson, LK
中科院分区：
文献类型：
--
作者：
Ramelot, TA;Gentile, LN;Nicholson, LK
淀粉样蛋白前体蛋白（APP）的胞质尾部似乎通过参与细胞内信号传导和APP的蛋白水解加工在细胞中发挥着两个重要作用。因此，了解APP的47个残基胞质尾部的结构对于理解正常细胞功能中涉及的分子相互作用以及阿尔茨海默病的发病机制具有重要意义。采用多维溶液核磁共振波谱法研究了含有两个n端残基（GS）和APP细胞质尾部的49个残基肽（APP- c）在4.2-7.1 pH范围内的结构特征。虽然肽不采用稳定的折叠结构，但在所检测的pH范围内存在不稳定结构区域，并通过h - α化学位移、NOE分析和(3)J（HNH α）偶联常数以及酰胺质子和滴定羧酸基团之间的瞬态氢键的鉴定来表征。这些研究扩展了其他人的工作[Kroenke et al. (1997) Biochemistry 36, 8145-8152]，通过在n端20个氨基酸残基中识别额外的新生螺旋和疏水簇，并进一步将TPEE转表征为螺旋盖盖盒。APP-C的瞬时结构揭示了细胞质尾部的预定顺序在控制胞质结合伙伴的特异性和亲和力方面的重要性。
The cytoplasmic tail of the amyloid precursor protein (APP) appears to play two important roles in the cell through participation in intracellular signaling and proteolytic processing of APP. Hence, knowledge of the structure of the 47 residue cytoplasmic tail of APP is important for understanding the molecular interactions involved in normal cell function as well as in the pathogenesis of Alzheimer's disease. Multidimensional solution NMR spectroscopy has been applied to examine the structural features of a 49-residue peptide (APP-C) containing two N-terminal residues (GS) and the APP cytoplasmic tail, over the pH range of 4.2-7.1. Although the peptide does not adopt a stable folded structure, regions of unstable structure exist over the pH range examined and have been characterized by a combination of H-alpha chemical shifts, NOE analysis, and (3)J(HNH alpha) coupling constants and by identification of transient hydrogen bonds between amide protons and titrating carboxylate groups. These studies extend the work of others [Kroenke et al. (1997) Biochemistry 36, 8145-8152] by identifying an additional nascent helix and a hydrophobic cluster within the N-terminal 20 amino acid residues and by further characterizing the TPEE turn as a helix capping box. The transient structure of APP-C provides insight into the importance of preordering of this cytoplasmic tail in governing specificity and affinity for cytosolic binding partners.