Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.
Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.
复制标题
爱荷华突变型β-淀粉样原纤维中新型β-折叠结构的证据。
DOI：
10.1021/bi9002666
复制
发表时间：
2009
期刊：
影响因子：
2.9
通讯作者：
Meredith,StephenC
中科院分区：
文献类型：
--
作者：
Tycko,Robert;Sciarretta,KimberlyL;Orgel,JosephPRO;Meredith,StephenC
β-淀粉样蛋白编码序列中的Asp23-to-Asn突变，称为爱荷华突变，与早发性家族性阿尔茨海默病和脑淀粉样血管病有关，其中患者主要发生突变肽的神经性斑块和大量血管沉积。我们通过电子显微镜、x射线衍射和固态核磁共振波谱检测了突变肽d23n - a - β40。d23n - a - β40形成原纤维的速度明显快于野生型肽（d23n - a - β40和野生型肽wt - a - β40的k分别为3.77 × 10−3min−1和1.07 × 10−4min−1），且无迟滞期。电镜显示d23n - a - β40形成多种形态的原纤维。x射线纤维衍射表现为交叉-β模式，在4.7 Å处有尖锐反射，在9.4 Å处有宽反射，明显小于wt - a -β 40原纤维的值（10.4 Å）。固态核磁共振测量表明原纤维的分子水平多态性，只有少数d23n - a - β40原纤维含有在wt - a - β40原纤维和大多数其他淀粉样原纤维中常见的登记内平行β片结构。通过13C - 13C和15n - 13C偶极子-偶极子偶极子耦合测量分子间距离，表明了大多数原纤维中的反平行β-片结构。存在一种有趣的可能性，即d23n - a - β40原纤维的异常结构与这些患者异常的血管增生临床表现之间存在关系。
Asp23-to-Asn mutation within the coding sequence of β-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer’s disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Aβ40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Aβ40 forms fibrils considerably faster than the wild-type peptide (k= 3.77 × 10−3min−1and 1.07 × 10−4min−1for D23N-Aβ40 and the wild-type peptide WT-Aβ40, respectively) and without a lag phase. Electron microscopy shows that D23N-Aβ40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-β pattern, with a sharp reflection at 4.7 Å and a broad reflection at 9.4 Å, which is notably smaller than the value for WT-Aβ40 fibrils (10.4 Å). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Aβ40 fibrils containing the in-register, parallel β-sheet structure commonly found in WT-Aβ40 fibrils and most other amyloid fibrils. Antiparallel β-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through13C−13C and15N−13C dipole−dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Aβ40 fibrils and the unusual vasculotropic clinical picture in these patients.