Medical implications of understanding the functions of human small heat shock proteins

Mymrikov, Evgeny V.; Haslbeck, Martin

doi:10.1586/14789450.2015.1039993

Cited by 11 publications

(10 citation statements)

References 136 publications

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“…Small heat shock proteins play a key role in protecting the cell from irreversible protein aggregation under diverse stress conditions (42,43) as well as aging (44). Members of the sHsp family are found in almost all living organisms, and the number of different sHsps is substantially increased in higher eukaryotes compared with prokaryotes and lower eukaryotes (5,45).…”

Section: Discussionmentioning

confidence: 99%

The Chaperone Activity and Substrate Spectrum of Human Small Heat Shock Proteins

Mymrikov

Daake

Richter

et al. 2017

Journal of Biological Chemistry

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132

154

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Edited by Norma AllewellSmall heat shock proteins (sHsps) are a ubiquitous family of molecular chaperones that suppress the unspecific aggregation of miscellaneous proteins. Multicellular organisms contain a large number of different sHsps, raising questions as to whether they function redundantly or are specialized in terms of substrates and mechanism. To gain insight into this issue, we undertook a comparative analysis of the eight major human sHsps on the aggregation of both model proteins and cytosolic lysates under standardized conditions. We discovered that sHsps, which form large oligomers (HspB1/Hsp27, HspB3, HspB4/␣A-crystallin, and HspB5/␣B-crystallin) are promiscuous chaperones, whereas the chaperone activity of the other sHsps is more substrate-dependent. However, all human sHsps analyzed except HspB7 suppressed the aggregation of cytosolic proteins of HEK293 cells. We identified ϳ1100 heat-sensitive HEK293 proteins, 12% of which could be isolated in complexes with sHsps. Analysis of their biochemical properties revealed that most of the sHsp substrates have a molecular mass from 50 to 100 kDa and a slightly acidic pI (5.4 -6.8). The potency of the sHsps to suppress aggregation of model substrates is correlated with their ability to form stable substrate complexes; especially HspB1 and HspB5, but also B3, bind tightly to a variety of proteins, whereas fewer substrates were detected in complex with the other sHsps, although these were also efficient in preventing the aggregation of cytosolic proteins.

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Section: Discussionmentioning

confidence: 99%

The Chaperone Activity and Substrate Spectrum of Human Small Heat Shock Proteins

Mymrikov

Daake

Richter

et al. 2017

Journal of Biological Chemistry

Self Cite

132

154

View full text Add to dashboard Cite

show abstract

“…Similar to their plant homologs, not all of them are able to form hetero-oligomers. The human sHsps can be divided roughly into two classes where most of the members only form hetero-oligomers within the same class (161,(163)(164)(165). Interestingly, however, some members seem to connect the two classes by their ability to interact with members of both classes.…”

Section: Substrate Recognitionmentioning

confidence: 99%

Small heat shock proteins: Simplicity meets complexity

Haslbeck

Weinkauf

Büchner

2019

Journal of Biological Chemistry

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228

218

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Edited by Norma M. Allewell Small heat shock proteins (sHsps) are a ubiquitous and ancient family of ATP-independent molecular chaperones. A key characteristic of sHsps is that they exist in ensembles of iso-energetic oligomeric species differing in size. This property arises from a unique mode of assembly involving several parts of the subunits in a flexible manner. Current evidence suggests that smaller oligomers are more active chaperones. Thus, a shift in the equilibrium of the sHsp ensemble allows regulating the chaperone activity. Different mechanisms have been identified that reversibly change the oligomer equilibrium. The promiscuous interaction with non-native proteins generates complexes that can form aggregate-like structures from which native proteins are restored by ATP-dependent chaperones such as Hsp70 family members. In recent years, this basic paradigm has been expanded, and new roles and new cofactors, as well as variations in structure and regulation of sHsps, have emerged. This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 1035. This is the fifth article in the JBC Reviews series "Molecular chaperones and protein quality control." The authors declare that they have no conflicts of interest with the contents of this article.

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“…It is widely accepted that PGC-1 promotes mitochondrial respiration through uncoupling protein-2 (UCP2), which in turn facilitates heat production by uncoupling oxidative phosphorylation [24,25]. Heat-shock proteins, on the other hand, serve as essential chaperons for protein folding and degradation [26,27].…”

Section: Introductionmentioning

confidence: 99%

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

Wang

Zheng

et al. 2015

Cardiovasc Toxicol

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Paraquat (1,1'-dim ethyl-4-4'-bipyridinium dichloride), a highly toxic quaternary ammonium herbicide widely used in agriculture, exerts potent toxic prooxidant effects resulting in multi-organ failure including the lung and heart although the underlying mechanism remains elusive. Recent evidence suggests possible involvement of endothelin system in paraquat-induced acute lung injury. This study was designed to examine the role of endothelin receptor A (ETA) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ETA receptor knockout mice were challenged to paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, as well as apoptosis and mitochondrial damage. Levels of the mitochondrial proteinsfor biogenesis and oxidative phosphorylation including UCP2, HSP90 and PGC1α were evaluated. Our results revealed that paraquat elicited cardiac enlargement, mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic and end-diastolic diameters as well as reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, overt apoptosis and mitochondrial damage. ETA receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ETA receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ETA receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.

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Medical implications of understanding the functions of human small heat shock proteins

Cited by 11 publications

References 136 publications

The Chaperone Activity and Substrate Spectrum of Human Small Heat Shock Proteins

The Chaperone Activity and Substrate Spectrum of Human Small Heat Shock Proteins

Small heat shock proteins: Simplicity meets complexity

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction

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