Identification by <sup>1</sup>H NMR spectroscopy of flexible C‐terminal extensions in bovine lens α‐crystallin

Carver, John A.; Aquilina, J. Andrew; Truscott, Roger J.W.; Ralston, G.B.

doi:10.1016/0014-5793(92)81386-z

Cited by 141 publications

(132 citation statements)

References 27 publications

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“…Rosenthal fibres accumulate as a result of insufficient protein degradation in the cell. Bc's lysine residues, particularly the three in the solventexposed and highly flexible C-terminal extension (K166, K175 and K174) [9] serve as potential sites for the binding of ubiquitin in order to target the protein for degradation [178][179][180]. The presence of Bc-ubiquitin conjugates in such pathological inclusions implies a breakdown of the cell's protein degradation system.…”

Section: The Role Of Shsps In Neurodegenerative Diseasementioning

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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180

177

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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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Section: The Role Of Shsps In Neurodegenerative Diseasementioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

Self Cite

180

177

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“…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. Furthermore, NMR measurements determined the diffusion coefficients of the native and fibrillar forms of αB-crystallin.…”

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

confidence: 99%

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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“…Abbreviations: sHSP, small heat-shock protein: rec-, recombinant; SP buffer, sodium phosphate buffer: DTT, dithiothreitol; CD, circular dichroism; BSA, bovine serum albumin domain which terminates in a short and flexible C-terminal tail [3,9,10]. Subunits generally assemble into large heterogeneous complexes (150-800 kDa), possibly in a flexible micellelike arrangement, with the hydrophobic N-terminal domains directed inward, and the polar C-terminal domains and tails extending into solution [11 14].…”

Section: Introductionmentioning

confidence: 99%

Caenorhabditis elegans small heat‐shock proteins Hsp12.2 and Hsp12.3 form tetramers and have no chaperone‐like activity

et al. 1998

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Four 12.2-12.6 kDa small heat-shock proteins (sHSPs) of Caenorhabditis elegans are the smallest known members of the sHSP family. They essentially comprise the characteristic C-terminal 'ct-crystallin domain' of the sHSPs, having a very short N-terminal region, and lacking a C-terminal tail. Recombinant Hspl2.2 and 12.3 are characterized here. Far-UV CD spectra reveal, as for other sHSPs, predominantly a [~-sheet structure. By gel permeation and crosslinking, they are the first sHSPs shown to occur as tetramers, rather than forming the usual large multimeric complexes. Exceptionally, too, both appear devoid of in vitro chaperone-like abilities. This supports the notion that tetramers are the building blocks of sHSP complexes, and that higher multimer formation, mediated through the N-terminal domains, is a prerequisite for chaperone-like activity.

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Identification by ¹H NMR spectroscopy of flexible C‐terminal extensions in bovine lens α‐crystallin

Cited by 141 publications

References 27 publications

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

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

Crystallin proteins and amyloid fibrils

Caenorhabditis elegans small heat‐shock proteins Hsp12.2 and Hsp12.3 form tetramers and have no chaperone‐like activity

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Identification by 1H NMR spectroscopy of flexible C‐terminal extensions in bovine lens α‐crystallin

Cited by 141 publications

References 27 publications

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

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

Crystallin proteins and amyloid fibrils

Caenorhabditis elegans small heat‐shock proteins Hsp12.2 and Hsp12.3 form tetramers and have no chaperone‐like activity

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Identification by ¹H NMR spectroscopy of flexible C‐terminal extensions in bovine lens α‐crystallin