Bielska Agata A, Zondlo Neal J
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Biochemistry. 2006 May 2;45(17):5527-37. doi: 10.1021/bi052662c.
Alzheimer's disease is characterized by two protein precipitates, extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). The primary constituent of NFTs is a hyperphosphorylated form of the microtubule-binding protein tau. Hyperphosphorylation of tau on over 30 residues, primarily within proline-rich sequences, is associated with conformational changes whose nature is poorly defined. Peptides derived from the proline-rich region of tau (residues 174-242) were synthesized, and the conformations were analyzed for the nonphosphorylated and phosphorylated peptides. CD and NMR data indicate that phosphorylation of serine and threonine residues in proline-rich sequences induces a conformational change to a type II polyproline helix. The largest phosphorylation-dependent conformational changes observed by CD were for tau peptides incorporating residues 174-183 or residues 229-238. Phosphoserine and phosphothreonine residues exhibited ordered values of (3)J(alphaN) (3.1-6.2 Hz; mean = 4.7 Hz) compared to nonphosphorylated serine and threonine. Phosphorylation of a tau peptide consisting of tau residues 196-209 resulted in the disruption of a nascent alpha-helix. These results suggest that global reorganization of tau may occur upon hyperphosphorylation of proline-rich sequences in tau.
阿尔茨海默病的特征是出现两种蛋白质沉淀物，即细胞外淀粉样斑块和细胞内神经原纤维缠结（NFTs）。NFTs的主要成分是微管结合蛋白tau的过度磷酸化形式。tau蛋白在30多个残基上发生过度磷酸化，主要发生在富含脯氨酸的序列中，这与构象变化有关，但其性质尚不清楚。合成了源自tau蛋白富含脯氨酸区域（残基174 - 242）的肽段，并对非磷酸化和磷酸化肽段的构象进行了分析。圆二色光谱（CD）和核磁共振（NMR）数据表明，富含脯氨酸序列中的丝氨酸和苏氨酸残基磷酸化会诱导构象转变为II型多聚脯氨酸螺旋。CD观察到的最大的磷酸化依赖性构象变化发生在包含残基174 - 183或残基229 - 238的tau肽段上。与非磷酸化的丝氨酸和苏氨酸相比，磷酸丝氨酸和磷酸苏氨酸残基的（3）J（αN）有序值为（3.1 - 6.2 Hz；平均值 = 4.7 Hz）。由tau蛋白残基196 - 209组成的tau肽段磷酸化导致新生α螺旋的破坏。这些结果表明，tau蛋白富含脯氨酸序列的过度磷酸化可能会导致tau蛋白的整体重组。
