Oligomerization preceding amyloid fibril formation: a process in common to intrinsically disordered and globular proteins

Abstract

Neurodegenerative diseases present a big burden to society. At the molecular level many of them - if not all - show protein aggregation (as an epiphenomenon or as a cause). The knowledge on details of thermodynamics and kinetics as well as structure of the protein aggregates, especially the early and soluble oligomers, may help in designing inhibitors for early stages of such diseases. Here, a possible outlook on more general mechanism for their formation is discussed. The oligomers of amyloid forming proteins, which are present prior and during nucleation and amyloid fibril formation, are claimed to be toxic to cells. Oligomers of the globular proteins and the intrinsically disordered proteins (IDPs), form in vitro upon partial denaturation and renaturation, respectively. Often they form if the sample is heated or freeze-thawed for a few cycles. A question is asked if this does not highlight one important property in common to globular proteins and IDPs, namely, a high energetic barrier dividing such oligomers from the monomers. This also would imply existence of two populations of states, one, the monomer - being metastable - at least under the conditions, which promote fibril formation.

Exploring the accessible conformations of N‐terminal acetylated α‐synuclein

“…Because amyloid deposits were first detected in brains of sick individuals, it was assumed that they were the neurotoxic species, but because amyloid is such a common structural motif, the ability to form amyloid is now considered a general property of a polypeptide in solution [105]. Over and over, conversion of IDPs into amyloid aggregates has not been observed to be a simple two‐state transition [106]. Oligomer formation has been established as an important mechanistic step in fibril formation, for example as in Alzheimer's disease [103,107].…”

Putative alternative functions of human stefin B (cystatin B): binding to amyloid‐beta, membranes, and copper

“…Stefin B was shown to populate folding intermediates at equilibrium, and it folded in 2 phases, whereas the slower one could arrive from molten globule intermediate to the folded dimeric state . It is speculated that oligomeric folding‐unfolding intermediates are at the cross‐road between folding and aggregation . Cystatins may be used as a model for an alternative mechanism of folding …”

Multiple Structural States Exist Throughout the Helical Nucleation Sequence of the Intrinsically Disordered Protein Stathmin, As Reported by Electron Paramagnetic Resonance Spectroscopy

“…5,6 Because of their innate instability, which stems from the relative magnitude of energy fluctuations inherent to biologically relevant temperatures, 7 these highly dynamic proteins typically explore a variety of conformations as monomers or, in some cases, adopt a lowest energy state as an oligomer or aggregate. 8,9 Stathmin, the primary member in a family of "stathmin-like" IDPs, is a ubiquitous cytoplasmic protein found in eukaryotic cells and is part of a signaling pathway to regulate cell proliferation, differentiation, and function by controlling micro-tubule growth. Its disregulation has also been directly linked to abnormal cell behavior and the proliferation of cancer tissue.…”

“…Although some IDPs are toxic or pathogenic (e.g., some forms of α-synuclein and amyloid-β), many of these highly flexible, unstructured proteins play important roles in cellular signaling and metabolic regulation . Since their discovery, IDPs have helped to reveal the strong link between protein flexibility and biological functionality, with “coupled folding and binding’” being a central theme in discussions of regulatory IDP behavior. , Because of their innate instability, which stems from the relative magnitude of energy fluctuations inherent to biologically relevant temperatures, these highly dynamic proteins typically explore a variety of conformations as monomers or, in some cases, adopt a lowest energy state as an oligomer or aggregate. , …”