Post by skyship on Mar 6, 2016 23:32:56 GMT -5
Many biologically active proteins act as specific oligomers. Structural proteins assemble into sophisticated supramolecular complexes that play various roles in a cell’s life. The formation of such functional oligomers and supramolecular complexes is tightly controlled and regulated. On the other hand, protein misfolding and subsequent uncontrolled (or unwanted) self-aggregation are known pathogens, which are now considered as potential driving forces for the development of a number of human diseases [1–6]. In fact, pathogenic proteinaceous deposits are at the heart of several so-called conformational diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), diffuse Lewy bodies disease, Lewy bodies variant of AD, dementia with Lewy bodies, multiple system atrophy, Hallervorden–Spatz disease, light chain-associated amyloidosis, light chain deposition disease, amyloidosis associated with hemodialysis, Huntington disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia, neuronal intranuclear inclusion disease, Creutzfeld–Jacob disease, Gerstmann–Straussler–Schneiker syndrome, fatal familial insomnia and Kuru. These, and many other diseases, originate from the conversion of soluble and harmless protein into stable, ordered, filamentous protein aggregates, commonly referred to as amyloid fibrils, which can accumulate in a variety of organs and tissues. At least 21 different proteins have been recognized as causative agents of these conformational diseases
there are several potential mechanisms of such cytotoxicity originating from protein deposition. These include: the disruption of the tissue architecture and functions promoted by the invasion of the extracellular space of organ by amyloids [8,18]; the destabilization of intracellular and extracellular membranes by oligomers, the formation of which may precede or coincide with the appearance of amyloid fibrils [19,20]; the apoptotic cell death and receptor-mediated toxicity triggered by the oligomer interaction with various neuronal receptors [21]; the oligomer-mediated impairment of the presynaptic P/Q-type calcium currents [22]; the impaired maturation of autophagosomes to lysosomes mediated by the oligomer accumulation [23]; the dysfunction of autophagy, a lysosomal pathway for degrading organelles and proteins [24]; the oxidative damage-induced disruption of the cell viability promoted by the incorporation of redox metals into amyloid fibrils and the subsequent generation of reactive oxygen species [25–29]; the general disorganization of cellular protein homeostasis associated with the exhaustion of the cell defense mechanisms, such as a chaperone system [30,31]; proteasome inhibition [32]; the loss of crucial protein function(s) and/or the gain of toxic function(s).
In addition to the amyloid fibrils discussed above, proteins can self-assemble to form several other types of aggregate, e.g. soluble oligomers and amorphous aggregates. Amorphous aggregates are typically formed faster than fibrils. There is no special conformational prerequisite for amorphous aggregation to occur, and many destabilized and partially unfolded proteins precipitate out of solution in a form of amorphous aggregate. On the other hand, fibrillation requires special conditions that promote the formation of the specific amyloidogenic conformations [39]. The choice between the three aggregation pathways, fibrillation, amorphous aggregate formation and oligomerization is determined by the amino acid sequence and by the peculiarities of protein environment.
Fibrils are proposed to be formed in template-dependent and template-independent manners (reviewed in [17]). In template-dependent fibrillation, interaction with a pre-existing template brings about conformational changes in an amyloidogenic protein, promoting its accommodation to the template with the subsequent exposure of the interactive regions for the consecutive self-assembly [40]. Here, the template is taken in a broad essence, as almost any conformational species involved in the amyloid fibrillation (i.e. altered monomeric conformation, oligomeric forms, immature fibrils, protofibrils and fragments of fibrils) could play this role.
Fibrils are proposed to be formed in template-dependent and template-independent manners (reviewed in [17]). In template-dependent fibrillation, interaction with a pre-existing template brings about conformational changes in an amyloidogenic protein, promoting its accommodation to the template with the subsequent exposure of the interactive regions for the consecutive self-assembly [40]. Here, the template is taken in a broad essence, as almost any conformational species involved in the amyloid fibrillation (i.e. altered monomeric conformation, oligomeric forms, immature fibrils, protofibrils and fragments of fibrils) could play this role.
Aβ oligomers
Among various amyloidogenetic proteins, oligomerization and its potential consequences are well documented for natural and synthetic Aβ peptides. Because various aspects of Aβ oligomer formation and toxicity were considered in a recent review by Sakono & Zako [49], only some key observations are presented below. Several different oligomeric forms, ranging from dimers to 24-mers and to higher relative molecular mass soluble species, have been reported for natural and synthetic Aβ peptides
www.ncbi.nlm.nih.gov/pmc/articles/PMC2916643/