distinct annular oligomers captured along the assembly and disassembly pathways of transthyretin amyloid protofibrils独特的环状低聚物捕获的装配和拆卸路径转体基因淀粉样原纤丝.pdfVIP

Distinct Annular Oligomers Captured along the Assembly and Disassembly Pathways of Transthyretin Amyloid Protofibrils 1,2 ´ ´ 3 2,4 2,4 ´ 1 Ricardo H. Pires *, Arpad Karsai , Maria J. Saraiva , Ana M. Damas *, Miklos S. Z. Kellermayer * 1 Department of Biophysics and Radiation Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary, 2 Institute for Molecular and Cell Biology, University ´ ´ ˆ ´ of Porto, Porto, Portugal, 3 Department of Biophysics, University of Pecs, Pecs, Hungary, 4 Instituto de Ciencias Biomedicas de Abel Salazar, University of Porto, Porto, Portugal Abstract Background: Defects in protein folding may lead to severe degenerative diseases characterized by the appearance of amyloid fibril deposits. Cytotoxicity in amyloidoses has been linked to poration of the cell membrane that may involve interactions with amyloid intermediates of annular shape. Although annular oligomers have been detected in many amyloidogenic systems, their universality, function and molecular mechanisms of appearance are debated. Methodology/Principal Findings: We investigated with high-resolution in situ atomic force microscopy the assembly and disassembly of transthyretin (TTR) amyloid protofibrils formed of the native protein by pH shift. Annular oligomers were the first morphologically distinct intermediates observed in the TTR aggregation pathway. Morphological analysis suggests that they can assemble into a double-stack of octameric rings with a 16 62 nm diameter, and displaying the tendency to form linear structures. According to lig