Work

Characteristics of Amyloid-Related Oligomers Revealed by Crystal Structures of Macrocyclic β-Sheet Mimics

Year: 2011

Type: article

Abstract: Protein amyloid oligomers have been strongly linked to amyloid diseases and can be intermediates to amyloid fibers. β-Sheets have been identified in amyloid oligomers. However, because of their transient and highly polymorphic properties, the details of their self-association remain elusive. Here we explore oligomer structure using a model system: macrocyclic peptides. Key amyloidogenic sequences from Aβ and tau were incorporated into macrocycles, thereby restraining them to β-strands, but limiting the growth of the oligomers so they may crystallize and cannot fibrillate. We determined the atomic structures for four such oligomers, and all four reveal tetrameric interfaces in which β-sheet dimers pair together by highly complementary, dry interfaces, analogous to steric zippers found in fibers, suggesting a common structure for amyloid oligomers and fibers. In amyloid fibers, the axes of the paired sheets are either parallel or antiparallel, whereas the oligomeric interfaces display a variety of sheet-to-sheet pairing angles, offering a structural explanation for the heterogeneity of amyloid oligomers.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja200222n

Authors: Cong Liu, Michael R. Sawaya, Pin-Nan Cheng, Jing Zheng, James S. Nowick, David Eisenberg

Institutions: Howard Hughes Medical Institute, University of California, Los Angeles, University of California, Irvine

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology (medical)

Field: Medicine

Domain: Health Sciences

Open Access status: green

Funders: Howard Hughes Medical Institute, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences

Awards: G1033211582, G2012103207, Structural Biology of Amyloid Disease, Chemical Models of Protein beta-Sheet Interactions