Mini-αB-Crystallin:  A Functional Element of αB-Crystallin with Chaperone-like Activity

Bhattacharyya, Jaya; Udupa, E. G. Padmanabha; Wang, Jing; Sharma, K. Krishna

doi:10.1021/bi0518141

Cited by 119 publications

(118 citation statements)

References 47 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Various studies have suggested that target protein binding is mediated by the N-terminal domain [95][96][97][98] or the ACD [99][100][101]. Indeed, with regards to the latter, we [18] and others [17,20,102] have shown that isolated ACDs exhibit chaperone function.…”

Section: The Chaperone Mechanism Of Shspsmentioning

confidence: 74%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

View full text Add to dashboard Cite

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.

show abstract

Section: The Chaperone Mechanism Of Shspsmentioning

confidence: 74%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

180

177

View full text Add to dashboard Cite

show abstract

“…We identified 19-to 20-mer sequences with chaperone function from aA-crystallin and aB-crystallin. 12,13 The individual amino acid, the location, and the chain length of the amino acid sequence are important determinants of the function of a specific peptide. For example, while a 19-mer peptide consisting of a 70 to 88 sequence of aA-crystallin is antiapoptotic, sequences 66 to 80 of a 15-mer peptide cause aggregation and toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…11 Potential sequences of a-crystallins that exhibit chaperone activity have been identified. 12,13 We previously identified a 19-mer sequence corresponding to beta3 and beta4 regions of aA-crystallin domain, which has similar chaperone activity in vitro to that of aA-crystallin. 12 Further studies have revealed that the 19-mer peptide sequence of aA-crystallin inhibits fibril formation of Ab-amyloid peptides and suppresses the toxic action of Ab-peptide in rat pheochromocytoma (PC12) cells.…”

mentioning

confidence: 99%

“…11 Similarly, interactive sequences consisting of residues 73 to 92 in aB-crystallin are able to prevent the aggregation of substrate proteins similar to the action of native aB-crystallin. 13 Transport systems that mediate the uptake of oligopeptides are known in mammalian cells. With respect to RPE, two novel Na þ -coupled transport systems for oligopeptides-namely, sodium-coupled oligopeptide transport system 1 and 2 (SOPT1 and SOPT2)-have been identified.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antiapoptotic Properties of α-Crystallin–Derived Peptide Chaperones and Characterization of Their Uptake Transporters in Human RPE Cells

Sreekumar

Chothe

Sharma

et al. 2013

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Sreekumar PG, Chothe P, Sharma KK, et al. Antiapoptotic properties of a-crystallin-derived peptide chaperones and characterization of their uptake transporters in human RPE cells. Invest Ophthalmol Vis Sci. 2013;54:278754: -279854: . DOI:10.1167 PURPOSE. The chaperone proteins, a-crystallins, also possess antiapoptotic properties. The purpose of the present study was to investigate whether 19 to 20-mer a-crystallin-derived mini-chaperone peptides (a-crystallin mini-chaperone) are antiapoptotic, and to identify their putative transporters in human fetal RPE (hfRPE) cells. METHODS.Cell death and caspase-3 activation induced by oxidative stress were quantified in early passage hfRPE cells in the presence of 19 to 20-mer aA-or aB-crystallin-derived or scrambled peptides. Cellular uptake of fluorescein-labeled, a-crystallin-derived mini-peptides and recombinant full-length aB-crystallin was determined in confluent hfRPE. The entry mechanism in hfRPE cells for a-crystallin mini-peptides was investigated. The protective role of polycaprolactone (PCL) nanoparticle encapsulated aB-crystallin mini-chaperone peptides from H 2 O 2 -induced cell death was studied.RESULTS. Primary hfRPE cells exposed to oxidative stress and either aA-or aB-crystallin minichaperones remained viable and showed marked inhibition of both cell death and activation of caspase-3. Uptake of full-length aB-crystallin was minimal while a time-dependent uptake of aB-crystallin-derived peptide was observed. The mini-peptides entered the hfRPE cells via the sodium-coupled oligopeptide transporters 1 and 2 (SOPT1, SOPT2). PCL nanoparticles containing aB-crystallin mini-chaperone were also taken up and protected hfRPE from H 2 O 2 -induced cell death at significantly lower concentrations than free aB-crystallin minichaperone peptide.CONCLUSIONS. aA-and aB-crystallin mini-chaperones offer protection to hfRPE cells and inhibit caspase-3 activation. The oligopeptide transporters SOPT1 and SOPT2 mediate the uptake of these peptides in RPE cells. Nanodelivery of aB-crystallin-derived mini-chaperone peptide offers an alternative approach for protection of hfRPE cells from oxidant injury.Keywords: a-crystallin, chaperone peptides, oxidative stress, RPE protection, oligopeptide transporters T he superfamily of small heat shock proteins (sHSPs) has attracted considerable attention in recent years because of its multifunctional cellular properties. The human genome encodes 10 members of the sHSP family, among which aAcrystallin and aB-crystallin are considered important members. 1 Both aA-and aB-crystallins have been studied extensively in the lens for their chaperone and related functions. However, recent studies have identified several novel functions for aA-and aBcrystallins in retina and other tissues in addition to their wellrecognized chaperone function. 2 Both a-crystallins are expressed in RPE cells and in the retina; higher expression of aBcrystallin was found in the RPE while aA-crystallin was found mostly in photoreceptors and astroglial and Mül...

show abstract

“…Thus, it can be concluded that the isolated peptides from αA-crystallin and αB-crystallin inhibit fibril formation by Aβ(1-40) by competing for this binding site with monomeric forms of Aβ(1-40) during its aggregation [102,140]. Significantly, this same peptide region appears to mediate the chaperone activity of αB-crystallin against a range of other disease-related, fibril-forming target proteins, including α-synuclein and β2-microglobulin [138,140]. At present, the development of therapeutics for Alzheimer's disease is largely focused on identifying inhibitors of fibril formation by Aβ peptides with some molecules that exhibit high inhibitory activity having progressed to stage III clinical trials [143][144][145].…”

Section: The Region(s) Of α-Crystallin Responsible For Target Proteinmentioning

confidence: 99%

Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

221

234

View full text Add to dashboard Cite

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.

show abstract

Mini-αB-Crystallin: A Functional Element of αB-Crystallin with Chaperone-like Activity

Cited by 119 publications

References 47 publications

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

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

Antiapoptotic Properties of α-Crystallin–Derived Peptide Chaperones and Characterization of Their Uptake Transporters in Human RPE Cells

Crystallin proteins and amyloid fibrils

Contact Info

Product

Resources

About