Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.

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Protein Misfolding, Functional Amyloid, and Human Disease

2.2.1. Polyisocyanates 6117 2.2.2. Polysilanes 6118 2.2.3. Polyacetylenes 6120 2.3. Foldamer-Based Helical Polymers 6124 2.3.1. Click Polymerization 6126 2.3.2. Ring-Closing Reaction 6126 2.4. Other Types of Helical Polymers 6127 2.4.1. π-Conjugated Helical Polymers 6127 2.4.2. Metallosupramolecular Helical Polymers 6128 2.5. Induced Helical Polymers 6130 2.5.1. Induced Helical Polyacetylenes 6130 2.5.2. Other Induced Helical Polymers and Oligomers 6132

Helical polymers: synthesis, structures, and functions

In this review, we describe the recent advances in supramolecular helical assemblies formed from chiral and achiral small molecules, oligomers (foldamers), and helical and nonhelical polymers from the viewpoints of their formations with unique chiral phenomena, such as amplification of chirality during the dynamic helically assembled processes, properties, and specific functionalities, some of which have not been observed in or achieved by biological systems. In addition, a brief historical overview of the helical assemblies of small molecules and remarkable progress in the synthesis of single-stranded and multistranded helical foldamers and polymers, their properties, structures, and functions, mainly since 2009, will also be described.

Supramolecular Helical Systems: Helical Assemblies of Small Molecules, Foldamers, and Polymers with Chiral Amplification and Their Functions

Amyloid fibrillogenesis: themes and variations.

Conformational constraints for amyloid fibrillation: the importance of being unfolded.

Aggregation of Ig light chains to form amyloid fibrils is a characteristic feature of light-chain amyloidosis, a light-chain deposition disease. A recombinant variable domain of the light chain SMA was used to form amyloid fibrils in vitro. Fibril formation was monitored by atomic force microscopy imaging. Single filaments 2.4 nm in diameter were predominant at early times; protofibrils 4.0 nm in diameter were predominant at intermediate times; type I and type II fibrils 8.0 nm and 6.0 nm in diameter, respectively, were predominant at the endpoints. The increase in number of fibrils correlated with increased binding of the fluorescent dye thioflavin T. The fibrils and protofibrils showed a braided structure, suggesting that their formation involves the winding of protofibrils and filaments, respectively. These observations support a model in which two filaments combine to form a protofibril, two protofibrils intertwine to form a type I fibril, and three filaments form a type II fibril.

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Jay S. Petrick

Papers

Monitoring the assembly of Ig light-chain amyloid fibrils by atomic force microscopy