Misfolding of Amyloidogenic Proteins and Their Interactions with Membranes

Abstract

In this paper, we discuss amyloidogenic proteins, their misfolding, resulting structures, and interactions with membranes, which lead to membrane damage and subsequent cell death. Many of these proteins are implicated in serious illnesses such as Alzheimer’s disease and Parkinson’s disease. Misfolding of amyloidogenic proteins leads to the formation of polymorphic oligomers and fibrils. Oligomeric aggregates are widely thought to be the toxic species, however, fibrils also play a role in membrane damage. We focus on the structure of these aggregates and their interactions with model membranes. Study of interactions of amlyoidogenic proteins with model and natural membranes has shown the importance of the lipid bilayer in protein misfolding and aggregation and has led to the development of several models for membrane permeabilization by the resulting amyloid aggregates. We discuss several of these models: formation of structured pores by misfolded amyloidogenic proteins, extraction of lipids, interactions with receptors in biological membranes, and membrane destabilization by amyloid aggregates perhaps analogous to that caused by antimicrobial peptides.

Early Events in the Amyloid Formation of the A546T Mutant of Transforming Growth Factor β-Induced Protein in Corneal Dystrophies Compared to the Nonfibrillating R555W and R555Q Mutants

“…55 Another interesting possibility is the existence of so-called native-like states, as documented in several cases. 53,56–59 Examples include insulin, 53 S6 from Thermus thermophiles , 56 and acylphosphatase from Sulfolobus solfataricus (Sso AcP). 57 The fibrillation of these proteins is initiated from oligomers consisting of conformational states that are thermodynamically distinct from the native state, but structurally similar to it.…”

Turncoat Polypeptides: We Adapt to Our Environment

“…An amyloidogenic or amyloid‐forming protein (Figure H) is a protein that misfolds upon certain conditions, and the misfolded structure experiences irreversible aggregation forming amyloid fibrils. They are mostly related to neurodegenerative diseases, but some functional amyloids have also been described …”

“…They are mostly relatedt on eurodegenerative diseases,b ut some functional amyloids have also been described. [27][28][29] Hereinafter,w ef ocus on three closely related types of sequences:c hameleon sequences, metamorphic proteins, and switchp eptides. We use the generic term "turncoat" polypeptides to encompass all of them.…”

Targeting Assembly and Disassembly of Protein Aggregates

“…The transition from a soluble, functional protein to misfolded, aggregation-prone species, and eventually to ordered or disordered aggregates, is promoted by protein-dependent (structural features, genetic or post-translational modifications/PTMs) and protein-independent factors (cellular, environmental stimuli) [8,9]. Aging is the most common cause of protein aggregation [10], with a continuous progression determined by subtle, chronic, pathological changes in cellular components.…”