Essential Role of the NH2-terminal WD/EPF Motif in the Phosphorylation-activated Protective Function of Mammalian Hsp27

Thériault, Jimmy R.; Lambert, Herman; Chávez-Zobel, Aura T.; Charest, Gabriel; Lavigne, Pierre; Landry, Jacques

doi:10.1074/jbc.m402325200

Cited by 105 publications

(119 citation statements)

References 53 publications

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“…Contrary to expectations, the higher s 20,w peak is broader than the lower s 20,w value peak, making it likely that there is a distribution of large oligomers of different sizes and/or shapes. This polydispersity is consistent with cryo-electron microscopy (17) and gel filtration studies (12)(13)(14)(15)(16).…”

Section: Phosphorylated Hsp27 Size and Molecular Chaperone Functionsupporting

confidence: 71%

“…Some in vitro studies concluded that the unphosphorylated oligomeric Hsp27 (or the murine isoform Hsp25) protects proteins against aggregation better than does the phosphorylation mimic (13,19,27), whereas others found no difference (16,28,29), and still other studies found that the mimic protects better than does the unphosphorylated wild type (27,30,31). In-cell studies found that phosphorylation of Hsp27 was essential for thermo-protection of actin filaments (32), and the Hsp27 phosphorylation mimic decreased inclusion body formation better than did unphosphorylated Hsp27 (33).…”

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confidence: 99%

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Phosphorylation Dependence of Hsp27 Multimeric Size and Molecular Chaperone Function

Hayes

Napoli

Mazurkie

et al. 2009

Journal of Biological Chemistry

121

106

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The molecular chaperone Hsp27 exists as a distribution of large oligomers that are disassembled by phosphorylation at Ser-15, -78, and -82. It is controversial whether the unphosphorylated Hsp27 or the widely used triple Ser-to-Asp phosphomimic mutant is the more active molecular chaperone in vitro. This question was investigated here by correlating chaperone activity, as measured by the aggregation of reduced insulin or ␣-lactalbumin, with Hsp27 self-association as monitored by analytical ultracentrifugation. Furthermore, because the phospho-mimic is generally assumed to reproduce the phosphorylated molecule, the size and chaperone activity of phosphorylated Hsp27 were compared with that of the phospho-mimic. Hsp27 was triply phosphorylated by MAPKAP-2 kinase, and phosphorylation was tracked by urea-PAGE. An increasing degree of suppression of insulin or ␣-lactalbumin aggregation correlated with a decreasing Hsp27 self-association, which was the least for phosphorylated Hsp27 followed by the mimic followed by the unphosphorylated protein. It was also found that Hsp27 added to pre-aggregated insulin did not reverse aggregation but did inhibit these aggregates from assembling into even larger aggregates. This chaperone activity appears to be independent of Hsp27 phosphorylation. In conclusion, the most active chaperone of insulin and ␣-lactalbumin was the Hsp27 (elongated) dimer, the smallest Hsp27 subunit observed under physiological conditions. Next, the Hsp27 phospho-mimic is only a partial mimic of phosphorylated Hsp27, both in self-association and in chaperone function. Finally, the efficient inhibition of insulin aggregation by Hsp27 dimer led to the proposal of two models for this chaperone activity.

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Section: Phosphorylated Hsp27 Size and Molecular Chaperone Functionsupporting

confidence: 71%

mentioning

confidence: 99%

Phosphorylation Dependence of Hsp27 Multimeric Size and Molecular Chaperone Function

Hayes

Napoli

Mazurkie

et al. 2009

Journal of Biological Chemistry

121

106

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“…Phosphorylation reduces the average oligomer size, and increases oligomeric polydispersity and rate of subunit exchange of αBc [98,[132][133][134], whereas it leads to a dramatic decrease in the size of Hsp27 oligomers, such that the triply phosphorylated isoform is predominately dimeric in solution [135,136]. Thus, under stress conditions, Hsp27 is phosphorylated, triggering dissociation of the high molecular mass Hsp27 oligomers [117,135,137,138] and an increase in the amount of exposed hydrophobicity on the newly formed Hsp27 dimers [139]. Phosphorylation also affects the cellular distribution of some sHsps.…”

Section: Phosphorylationmentioning

confidence: 99%

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

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

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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“…However, even in the young lens, αB-crystallin is extensively phosphorylated [113,118]. All three sites of serine phosphorylation of Hsp27 are mediated by MAPKAP kinases [119,120]. In the brain, some of the αB-crystallin isolated from the proteinaceous aggregates of patients with degenerative diseases [121], amyloid plaques and Lewy bodies is phosphorylated [68].…”

Section: The Effect Of Post-translational Modifications On the Chapermentioning

confidence: 99%

Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

220

234

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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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Essential Role of the NH2-terminal WD/EPF Motif in the Phosphorylation-activated Protective Function of Mammalian Hsp27

Cited by 105 publications

References 53 publications

Phosphorylation Dependence of Hsp27 Multimeric Size and Molecular Chaperone Function

Phosphorylation Dependence of Hsp27 Multimeric Size and Molecular Chaperone Function

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

Crystallin proteins and amyloid fibrils

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