Departments of Biological Chemistry and Chemistry and Biochemistry, Molecular Biology Institute, Box 951570, UCLA, Howard Hughes Medical Institute, UCLA-DOE Institute, Los Angeles, California, 90095-1570.
Protein Sci. 2018 Jul;27(7):1295-1303. doi: 10.1002/pro.3420. Epub 2018 Jun 13.
Amyloid diseases are characterized by the deposition of proteins in the form of amyloid fibrils, in organs that eventually fail. The development of effective drug candidates follows from the understanding of the molecular processes that lead to protein aggregation. Here, we study amyloidogenic segments of transthyretin (TTR). TTR is a transporter of thyroxine and retinol in the blood and cerebrospinal fluid. When mutated and/or as a result of aging, TTR aggregates into amyloid fibrils that accumulate in organs such as the heart. Recently, we reported two amyloidogenic segments that drive amyloid aggregation. Here, we report the crystal structure of another six amyloidogenic segments of TTR. We found that the segments from the C-terminal region of TTR form in-register steric-zippers with highly-interdigitated, wet interfaces, whereas the β-strand B from the N-terminal region of TTR forms an out-of-register assembly, previously associated with oligomeric formation. Our results contribute fundamental information for understanding the mechanism of aggregation of TTR.
淀粉样变性疾病的特征是蛋白质以淀粉样纤维的形式在器官中沉积，最终导致这些器官衰竭。有效的候选药物的开发源于对导致蛋白质聚集的分子过程的理解。在这里，我们研究转甲状腺素蛋白（TTR）的淀粉样变性片段。TTR 是血液和脑脊液中甲状腺素和视黄醇的转运蛋白。当突变和/或由于衰老，TTR 聚集成淀粉样纤维，在心脏等器官中积累。最近，我们报道了两个驱动淀粉样聚集的淀粉样变性片段。在这里，我们报告了 TTR 的另外六个淀粉样变性片段的晶体结构。我们发现 TTR C 末端区域的片段形成了具有高度交错的、湿润的界面的顺式拉链，而 TTR N 末端的β-链 B 形成了一个之前与寡聚体形成相关的非对齐组装。我们的结果为理解 TTR 聚集的机制提供了基本信息。
