title: The formation, function and regulation of amyloids: insights from structural biology.
abstract: Amyloid diseases are characterized by the accumulation of insoluble, β-strand-rich aggregates. The underlying structural conversions are closely associated with cellular toxicity, but can also drive the formation of functional protein assemblies. In recent years, studies in the field of structural studies have revealed astonishing insights into the origins, mechanisms and implications of amyloid formation. Notably, high-resolution crystal structures of peptides in amyloid-like fibrils and prefibrillar oligomers have become available despite their challenging chemical nature. Nuclear magnetic resonance spectroscopy has revealed that dynamic local polymorphisms in the benign form of the prion protein affect the transformation into amyloid fibrils and the transmissibility of prion diseases. Studies of the structures and interactions of chaperone proteins help us to understand how the cellular proteostasis network is able to recognize different stages of aberrant protein folding and prevent aggregation. In this review, we will focus on recent developments that connect the different aspects of amyloid biology and discuss how understanding the process of amyloid formation and the associated defence mechanisms can reveal targets for pharmacological intervention that may become the first steps towards clinically viable treatment strategies.
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Landreh
authors.affiliation: Departments of Biological Chemistry and Chemistry & Biochemistry, Howard Hughes Medical Institute, UCLA-DOE Institute, Los Angeles, CA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Hipp
authors.affiliation: Departments of Biological Chemistry and Chemistry & Biochemistry, Howard Hughes Medical Institute, UCLA-DOE Institute, Los Angeles, CA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Eisenberg
authors.affiliation: Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.|Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wüthrich
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: F U
authors.initials: FU
authors.lastname: Hartl
mesh_terms: D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry / Q000502:physiology*; D000686:Amyloidosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D006801:Humans; D018832:Molecular Chaperones / Q000502:physiology; D015394:Molecular Structure; D017510:Protein Folding
chemical_list: D000682:Amyloid; D018832:Molecular Chaperones
keywords: NMR spectroscopy; X-ray crystallography; chaperones; conformational disease; prion proteins; protein aggregation