Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions

Abstract

Figure 1Funnels representing an idealized energy landscape for protein folding (a) or a rugged energy landscape with kinetic traps (b), from models of Dill and Chan (80). (a) The unfolded chain starts at the top of an energy landscape, and, as it forms intrachain contacts, lowering its free energy (and descending the funnel), the number of conformations it can sample is progressively reduced, thus eliminating the need for a global search. Ultimately, it reaches the unique native state at the energetic minimum. Note that the number of pathways typically available coming down from the unfolded state may not be unlimited, as depicted here, but may be multiple. (b) Descending a rugged landscape, the polypeptide can lodge in a kinetic trap or can alternatively descend through a narrow path to the native state. Molecular chaperones may act to "smooth" rugged landscapes, preventing polypeptide from descending into a kinetic trap, or rescuing it from one. Reproduced with permission from Nature Structural Biology (80). N, native state.

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

“…We have hypothesized that the loss of native state stability leads to the formation and accumulation of a partially unfolded, aggregation-prone species, resulting in fibrillization. This is supported by an earlier study showing that expansion of a polyglutamine tract inserted into myoglobin results in a progressive loss of conformational stability of the protein (22) and is also concordant with the generalized model of protein misfolding associated with a wider variety of conformational diseases (11,12,28,29).…”

“…In previous work, it has been suggested by ourselves and others that expansion of the polyglutamine tract may destabilize the native protein, leading to aggregation and fibrillization (19,22,24). This follows the generally accepted paradigm of protein misfolding diseases, in which the native conformation of a protein is destabilized by mutation, resulting in aberrant folding pathways and accumulation of a partially folded, aggregation-prone intermediate through which fibrils are formed (11,12,28,29) (Fig. 7A).…”

Mitochondria maintain maturation and secretion of lipoprotein lipase in the endoplasmic reticulum

“…Notably, protein misfolding is considered to be a cause and/ or consequence of numerous diseases [16,17], including diabetes mellitus [18]. The latter is known to be associated with mitochondrial dysfunction that becomes obvious by increased free radical production [19] and altered mitochondrial Ca 2+ homoeostasis [20].…”

The Role of Protein Misfolding in the Pathogenesis of Human Diseases

“…In this model, fibril formation is preceded by a concentration-dependent 'lag' period, after which a nucleation event occurs and fibril formation proceeds rapidly. The ratelimiting stage in the reaction is the formation of the energetically unfavorable nucleus (16). As highlighted by Kelly, unlike classical polymerization kinetics, fibrillogenesis nucleation is thought not to be preceded by the swift addition of monomers to the growing nucleus (17).…”

“…Additionally, low levels of denaturant and alterations in pH have also been shown to lead to fibril formation in vitro (24 -27). As recently comprehensively reviewed (16), analysis of TTR and prion fibrillogenesis argues strongly for a decrease in kinetic stability rather than thermodynamic destabilization as the most common energetic driving force of fibrillogenesis. That is, destabilization results from a change in the energy barrier between the native and unfolded states, rather than an alteration in the free energy difference between the unfolded and the native state (16).…”