Crystallin proteins and amyloid fibrils

Abstract

Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, alpha-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of alpha B-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials. Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.

Small heat-shock proteins: important players in regulating cellular proteostasis

“…This model is favoured because (i) the dissociated species would expose more surface hydrophobicity to solution and therefore be more capable of binding to destabilised target proteins and, (ii) the chaperone activity of sHsps is dependent on subunit exchange. Recent work, including our own, has shed further light on the multi-faceted manner by which sHsps interact with aggregation-prone proteins, particularly those aggregating to form amyloid fibrils (reviewed in [30]). In summary, this work has demonstrated that sHsps can interact with monomeric, oligomeric, prefibrillar and fibrillar forms of target protein in order to prevent their aggregation, i.e.…”

Biophysical chemistry of the ageing eye lens

“…While the lens has many systems and special characteristics that are engineered to prevent this aggregation, the effectiveness of these systems tends to diminish as the lens ages (Bloemendal et al 2004;Ecroyd and Carver 2009;). Over time, proteins tend to accumulate posttranslational modifications, due to either external damage such as UV radiation exposure or exposure to heat, or by one of several spontaneous chemical modification pathways to which proteins are susceptible (Hains and Truscott 2007;Lampi et al 1998).…”

“…Under normal circumstances, proteins fold rapidly from an unstructured chain to their native states and thus avoid mutual interaction between partially unfolded intermediates. When proteins are exposed to stress conditions, however, the equilibrium between the native and unfolded states is disrupted which can cause the protein to occupy these intermediate states for longer periods of time (Ecroyd and Carver 2009;Haslbeck and Vierling 2015).…”

“…These proteins are highly efficient chaperones, which act to prevent protein aggregation by Fig. 3 Protein folding, unfolding and off-folding (aggregation) pathways (Ecroyd and Carver 2009) binding to unfolded and partially folded proteins, preventing their association with other unstable proteins (Fu 2014). In this way, they act as a first line of defence against protein unfolding and aggegation (Ecroyd and Carver 2009;Haslbeck and Vierling 2015).…”

“…Cataract occurs when these proteins aggregate into large bodies which cause light scattering and loss of visual acuity (Moreau and King 2012). While the lens has systems to prevent protein aggregation (Ecroyd and Carver 2009;Horwitz 2003), the build-up of damaging modifications over time will eventually overwhelm them and aggregate formation results. Cataract has become an inevitable reality of ageing, especially as the lifetimes of individuals increases (Michael and Bron 2011).…”