Characterisation of Amyloid Fibril Formation by Small Heat-shock Chaperone Proteins Human αA-, αB- and R120G αB-Crystallins

Meehan, Sarah; Knowles, Tuomas P. J.; Baldwin, Andrew J.; Smith, J. F.; Squires, Adam M.; Clements, P.; Treweek, Teresa M.; Ecroyd, Heath; Tartaglia, Gian Gaetano; Vendruscolo, Michele; MacPhee, Cait E.; Dobson, Christopher M.; Carver, John A.

doi:10.1016/j.jmb.2007.06.060

Cited by 92 publications

(111 citation statements)

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“…In transfected cardiomyocytes, the presence of these two sHsps also restored ubiquitin/proteasome activity and cell viability [151]. Our work has also shown that recombinant R120G αB-crystallin forms amyloid fibrils readily [152]. In a recent innovation, Muchowski et al [92] have developed a transgenic mouse in which the proteins associated with Parkinson's and Huntington's diseases (α-synuclein and a huntingtin fragment respectively) are expressed in the lens leading to their aggregation and cataract formation.…”

Section: In Vitro and In Vivo Formation Of Amyloid Fibrils By Crystalmentioning

confidence: 58%

“…The advantage of crystallin proteins is their ready availability in significant quantity which is of particular importance if amyloid fibrils are to be used for commercial purposes. As described above, individual α-and γ-crystallin subunits readily form fibrils under mildly denaturing conditions [152,155] as do the individual α-, β-and γ-crystallin classes [153]. Our recent work has shown that semi-pure and crude mixtures of the crystallins from bovine, ovine and deer lenses formed amyloid fibrils under similar conditions employed for the preparation of crystallin fibrils, i.e.…”

Section: Crystallin Proteins As Bionanomaterialsmentioning

confidence: 98%

“…Recently, Papankolopoulou et al [155] showed that wild type human γD-crystallin, along with its individual N-and C-terminal domains, formed well-defined amyloid fibrils when incubated at pH 3. Our recent work [152] has investigated in detail, using a range of biophysical techniques, fibril formation by the individual α-crystallin subunits and R120G αB-crystallin. In particular, NMR spectroscopy was used to show that the short and highly mobile C-terminal extension of αB-crystallin [156] maintains its flexibility in the fibrillar state.…”

Section: In Vitro and In Vivo Formation Of Amyloid Fibrils By Crystalmentioning

confidence: 99%

“…If present, however, they may be mixed in with amorphously aggregated crystallin proteins. Interestingly, αA-and αB-crystallin are as susceptible to fibril formation as the β-and γ-crystallins [152,153]. Thus, even the molecular chaperones αA-and αB-crystallin, which are highly stable proteins (like the other crystallins), are prone to aggregate and form fibrils, despite their role in protein stabilization in the lens.…”

Section: In Vitro and In Vivo Formation Of Amyloid Fibrils By Crystalmentioning

confidence: 99%

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Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

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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.

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Section: In Vitro and In Vivo Formation Of Amyloid Fibrils By Crystalmentioning

confidence: 58%

Section: Crystallin Proteins As Bionanomaterialsmentioning

confidence: 98%

Section: In Vitro and In Vivo Formation Of Amyloid Fibrils By Crystalmentioning

confidence: 99%

Section: In Vitro and In Vivo Formation Of Amyloid Fibrils By Crystalmentioning

confidence: 99%

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Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

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221

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“…Under physiological conditions, human Bc forms large roughly spherical assemblies of 8-18 nm in diameter [7,23]. Under partially denaturing conditions and elevated temperature, Bc also assembles into amyloid fibrils as revealed by TEM and atomic force microscopy [24,25].…”

mentioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

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Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of posttranslational modifications in sHsp chaperone function, particularly in the context of disease. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract (word count = 159)Small heat-shock proteins (sHsps) are a diverse family of intracellular molecular chaperone proteins that play a critical role in preventing protein unfolding, misfolding and aggregation, particularly under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) and thereby avoid the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. There has been much research into the structure and mechanism of chaperone action of sHsps over approximately the past 30 years, and significant progress has been made of late, however, there are still many unanswered questions relating to these aspects of sHsps. In this review, we outline some of the recent advances in understanding the structure and function of mammalian sHsps, particularly in the context of their many and varied roles in disease.

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NMR Studies of Eye Lens Crystallins

Martin

2014

eMagRes

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The crystallins of the eye lens are highly stable, soluble proteins that generate the refractive index gradient of the lens. In their native context, the crystallins form large soluble oligomers; a loss in solubility due to mutation, UV light damage, or chemical modification results in cataract. There are two broad classes of ubiquitous crystallin proteins; βγ -crystallins, which are purely structural, and the α-crystallins, which additionally play a chaperone role, maintaining solubility of compromised proteins in the lens. NMR methods have been used to investigate many structural and functional properties of both types of crystallins. Structures have been solved for many of the crystallins using both solid-state and solution NMRs, and these detailed molecular pictures have been used as a starting point for investigating conformational dynamics and intermolecular interactions.

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Characterisation of Amyloid Fibril Formation by Small Heat-shock Chaperone Proteins Human αA-, αB- and R120G αB-Crystallins

Cited by 92 publications

References 66 publications

Crystallin proteins and amyloid fibrils

Crystallin proteins and amyloid fibrils

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

NMR Studies of Eye Lens Crystallins

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