Institute for Biochemistry and Biotechnology, Technical Biochemistry, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
J Biol Chem. 2012 Jun 29;287(27):22662-71. doi: 10.1074/jbc.M112.362327. Epub 2012 May 8.
Oculopharyngeal muscular dystrophy is a late-onset disease caused by an elongation of a natural 10-alanine segment within the N-terminal domain of the nuclear poly(A)-binding protein 1 (PABPN1) to maximally 17 alanines. The disease is characterized by intranuclear deposits consisting primarily of PABPN1. In previous studies, we could show that the N-terminal domain of PABPN1 forms amyloid-like fibrils. Here, we analyze fibril formation of full-length PABPN1. Unexpectedly, fibril formation was independent of the presence of the alanine segment. With regard to fibril formation kinetics and resistance against denaturants, fibrils formed by full-length PABPN1 had completely different properties from those formed by the N-terminal domain. Fourier transformed infrared spectroscopy and limited proteolysis showed that fibrillar PABPN1 has a structure that differs from native PABPN1. Circumstantial evidence is presented that the C-terminal domain is involved in fibril formation.
眼咽型肌营养不良症是一种由核多聚腺苷酸结合蛋白 1（PABPN1）的 N 端结构域内的天然 10 个丙氨酸段延长至最多 17 个丙氨酸引起的迟发性疾病。该疾病的特征是核内沉积物主要由 PABPN1 组成。在之前的研究中，我们可以证明 PABPN1 的 N 端结构域形成淀粉样原纤维。在这里，我们分析全长 PABPN1 的原纤维形成。出乎意料的是，原纤维的形成并不依赖于丙氨酸段的存在。关于原纤维形成动力学和对变性剂的抗性，全长 PABPN1 形成的原纤维与 N 端结构域形成的原纤维具有完全不同的性质。傅里叶变换红外光谱和有限蛋白酶解表明，纤维状 PABPN1 的结构与天然 PABPN1 不同。有间接证据表明 C 端结构域参与了原纤维的形成。
