Chaperone networks in protein disaggregation and prion propagation

Winkler, Juliane; Tyedmers, Jens; Bukau, Bernd; Mogk, Axel

doi:10.1016/j.jsb.2012.05.002

Cited by 123 publications

(131 citation statements)

References 112 publications

(138 reference statements)

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“…In yeast and plants, members of the Hsp100 protein family regulate heat-induced protein aggregation by reversing amorphous and amyloid aggregates (33,(52)(53)(54)(55)(56)(57). These so-called disaggregases are essential for thermotolerance (34,(58)(59)(60).…”

Section: Heat-induced Aggregation Of Prion-like Proteins Is Reversed mentioning

confidence: 99%

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin-proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome. molecular chaperones | proteostasis | Dictyostelium discoideum | protein aggregation | prion

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Section: Heat-induced Aggregation Of Prion-like Proteins Is Reversed mentioning

confidence: 99%

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Orthologs of the Class I subfamily with an M-domain exist in bacteria (ClpB), yeast (Hsp104), and plants (Hsp101) (Lee et al 1994, Queitsch et al 2000, Cagliari et al 2011), all of which are heat-induced and implicated in protein unfolding/disaggregation and degradation (Schirmer et al 1996, Glover and Lindquist 1998, Dougan et al 2002, Hodson et al 2012, Winkler et al 2012a. Surprisingly, metazoans lack a bona fide ClpB/Hsp100-like disaggregase in their cytosol (see below).…”

Section: Clpb/hsp104 a Subfamily Of Hsp100mentioning

confidence: 99%

Disaggregases, molecular chaperones that resolubilize protein aggregates

Mokry

Abrahão

Ramos

2015

An. Acad. Bras. Ciênc.

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The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

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“…"foldase" activity Kim et al, 2013). Some molecular chaperones can also disaggregate protein aggregates (Weibezahn et al, 2005;Winkler et al, 2012;Hodson et al, 2012) or cooperate with proteases to facilitate protein degradation (Pickart and Cohen, 2004;Alexopoulos et al, 2012;Li and Lucius, 2013).…”

Section: Introductionmentioning

confidence: 99%

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Cappelli

Penco²,

Mannini³

et al. 2016

Biological Chemistry

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. (2016). Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations. Biological Chemistry: official scientific journal of the GBM, 397 (5), 401-415. Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations AbstractLiving systems protect themselves from aberrant proteins by a network of chaperones. We have tested in vitro the effects of different concentrations, ranging from 0 to 16 μm, of two molecular chaperones, namely αB-crystallin and clusterin, and an engineered monomeric variant of transthyretin (M-TTR), on the morphology and cytotoxicity of preformed toxic oligomers of HypF-N, which represent a useful model of misfolded protein aggregates. Using atomic force microscopy imaging and static light scattering analysis, all were found to bind HypF-N oligomers and increase the size of the aggregates, to an extent that correlates with chaperone concentration. SDS-PAGE profiles have shown that the large aggregates were predominantly composed of the HypF-N protein. ANS fluorescence measurements show that the chaperone-induced clustering of HypF-N oligomers does not change the overall solvent exposure of hydrophobic residues on the surface of the oligomers. αB-crystallin, clusterin and M-TTR can diminish the cytotoxic effects of the HypF-N oligomers at all chaperone concentration, as demonstrated by MTT reduction and Ca2+ influx measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasizes the efficiency and versatility of these protein molecules. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsCappelli, S., Penco, A., Mannini, B., Cascella, R., Wilson, M. R., Ecroyd, H., Li, X., Buxbaum, J. N., Dobson, C. M., Cecchi, C., Relini, A. & Chiti, F. (2016 measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasises the efficiency and versatility of these protein molecules.

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Chaperone networks in protein disaggregation and prion propagation

Cited by 123 publications

References 112 publications

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Disaggregases, molecular chaperones that resolubilize protein aggregates

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

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