A polymer physics perspective on driving forces and mechanisms for protein aggregation

Abstract

Protein aggregation is a commonly occurring problem in biology. Cells have evolved stress-response mechanisms to cope with problems posed by protein aggregation. Yet, these quality control mechanisms are overwhelmed by chronic aggregation-related stress and the resultant consequences of aggregation become toxic to cells. As a result, a variety of systemic and neurodegenerative diseases are associated with various aspects of protein aggregation and rational approaches to either inhibit aggregation or manipulate the pathways to aggregation might lead to an alleviation of disease phenotypes. To develop such approaches, one needs a rigorous and quantitative understanding of protein aggregation. Much work has been done in this area. However, several unanswered questions linger, and these pertain primarily to the actual mechanism of aggregation as well as to the types of intermolecular associations and intramolecular fluctuations realized at low protein concentrations. It has been suggested that the concepts underlying protein aggregation are similar to those used to describe the aggregation of synthetic polymers. Following this suggestion, the relevant concepts of polymer aggregation are introduced. The focus is on explaining the driving forces for polymer aggregation and how these driving forces vary with chain length and solution conditions. It is widely accepted that protein aggregation is a nucleation-dependent process. This view is based mainly on the presence of long times for the accumulation of aggregates and the elimination of these lag times with "seeds". In this sense, protein aggregation is viewed as being analogous to the aggregation of colloidal particles. The theories for polymer aggregation reviewed in this work suggest an alternative mechanism for the origin of long lag times in protein aggregation. The proposed mechanism derives from the recognition that polymers have unique dynamics that distinguish them from other aggregation-prone systems such as colloidal particles.

Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues

“…Here, T denotes temperature, and k is Boltzmann's constant. The radius of gyration of a g residue blob scales as g 1/2 , and for sequences lacking in proline residues, g ∼ 5 (20). The overall charge asymmetry is defined as , such that 0 ≤ κ ≤ 1.…”

A comparative analysis of the folding and misfolding pathways of the third PDZ domain of PSD95 investigated under different pH conditions

“…It has been suggested that the concepts underlying protein aggregation might be similar to those describing the organization of synthetic polymers, which may explain some features of the growth-kinetic processes [2]. A recent study has put forward a general unifying mechanism based on the formulation of master equations that describe the kinetics of fibrillar self-assembling as resulting from three basic processes: i) a nucleationdependent polymerization reaction (lag-phase), usually slower than the ii) elongation of preexisting nuclei, and finally iii) a secondary nucleation event deriving from the fragmentation of fibrils [3].…”

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

“…The aggregation process is often characterized by the presence of one or more threshold concentrations at which a sharp, discontinuous change to some aspect of the assembly state (e.g., size, conformational characteristics, material properties) occurs (3)(4)(5)(6). Such a change can be described using the concepts of phase transitions.…”

“…Phase separation, a subcategory of phase transitions, has recently received considerable attention due to increasing recognition of its importance in cell biology (7)(8)(9)(10)(11)(12)(13). Phase separation refers to aggregation-related changes in molecular density that give rise to the coexistence of dilute macromolecule-deficient phases and dense macromolecule-rich phases (3,14,15). Examples of multiple coexisting phases have been observed in biological contexts (15)(16)(17)(18), and these phases can be liquid, solid, or semisolid (e.g., a gel) (10,(19)(20)(21)(22)(23)(24)(25).…”