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

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors a...

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade

Alzheimer's disease (AD) pathogenesis is widely believed to be driven by the production and deposition of the amyloid-beta peptide (Abeta). For many years, investigators have been puzzled by the weak to nonexistent correlation between the amount of neuritic plaque pathology in the human brain and the degree of clinical dementia. Recent advances in our understanding of the development of amyloid pathology have helped solve this mystery. Substantial evidence now indicates that the solubility of Abeta, and the quantity of Abeta in different pools, may be more closely related to disease state. The composition of these pools of Abeta reflects different populations of amyloid deposits and has definite correlates with the clinical status of the patient. Imaging technologies, including new amyloid imaging agents based on the chemical structure of histologic dyes, are now making it possible to track amyloid pathology along with disease progression in the living patient. Interestingly, these approaches indicate that the Abeta deposited in AD is different from that found in animal models. In general, deposited Abeta is more easily cleared from the brain in animal models and does not show the same physical and biochemical characteristics as the amyloid found in AD. This raises important issues regarding the development and testing of future therapeutic agents.

Alzheimer's Disease and the Amyloid-β Peptide

Propagation of Tau Misfolding from the Outside to the Inside of a Cell

https://parkerlab.bio.uci.edu/publication%20attachments/2005_demuro_mina_kayed_milton_parker_glabe_133.pdf

Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers.

Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases

A structure-based approach to the mechanism of ion pumping in bacteriorhodopsin (BR) has fostered new hypotheses for the detailed molecular changes that underlie ion transport in this light-driven pump. Isomerization of the retinal from all-trans to 13-cis in response to absorption of the energy of a photon is thought to lead to proton transfer from the initially protonated Schiff base to an anionic aspartate residue (Asp85) in the first half of the BR photocycle. In this traditional view the proton is transferred directly from the Schiff base to Asp85. A comparison of structures of photocycle intermediates trapped shortly after proton transfer to Asp85 to those of the resting state suggested an alternative view for the mechanism of proton transfer. In this scenario, a local water molecule in hydrogen bond contact with the Schiff base and Asp85 in the resting state is destabilized upon isomerization of the retinal. The destabilized water loses a proton to Asp85 and the remaining hydroxyl anion migrates toward the positively charged Schiff base to abstract its proton. This mechanism, in which a hydroxyl ion is pumped in lieu of a proton, has now been challenged by interpretations of new structures for photointermediates that immediately precede and follow the deprotonation/protonation reaction. However, in contrast to the older structures in which photointermediates were prepared at room temperature, the new structures were obtained by illuminating wild-type BR in frozen crystals. The results of spectroscopic studies of BR suggest that the structures of intermediates trapped at low temperature may not be the same as native photocycle intermediates at room temperature. The precise mechanism of ion transfer in BR is therefore unresolved.

Brian W Edmonds

Papers

Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases

Atomic resolution structures and the mechanism of ion pumping in bacteriorhodopsin.