Hsp27 suppresses the Cu2+-induced amyloidogenicity, redox activity, and cytotoxicity of α-synuclein by metal ion stripping

Asthana, Abhishek; Madhuri, Bollapalli; Tangirala, Ramakrishna; Raman, Bakthisaran; Rao, Ch. Mohan

doi:10.1016/j.freeradbiomed.2014.04.012

Cited by 16 publications

(14 citation statements)

References 62 publications

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“…The H124K mutant delays aggregation of α-lactalbumin slightly longer than WT protein. This contrasts with the dramatic increase in chaperone activity reported for the analogous H104 mutation in HSPB5 (Rajagopal et al 2015b) coordinate metal ions (Asthana et al 2014;Mainz et al 2012), the concentration of which may depend on cellular stress conditions. Several charged residues in the HSPB5-ACD, including His104, are implicated in copper and zinc ion binding, and this binding affects dimer stability, oligomeric propensity, and chaperone function (Mainz et al 2012).…”

Section: Discussioncontrasting

confidence: 69%

pH-dependent structural modulation is conserved in the human small heat shock protein HSBP1

Clouser

Klevit

2017

Cell Stress and Chaperones

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The holdase activity and oligomeric propensity of human small heat shock proteins (sHSPs) are regulated by environmental factors. However, atomic-level details are lacking for the mechanisms by which stressors alter sHSP responses. We previously demonstrated that regulation of HSPB5 is mediated by a single conserved histidine over a physiologically relevant pH range of 6.5-7.5. Here, we demonstrate that HSPB1 responds to pH via a similar mechanism through pHdependent structural changes that are induced via protonation of the structurally analogous histidine. Results presented here show that acquisition of a positive charge, either by protonation of His124 or its substitution by lysine, reduces the stability of the dimer interface of the α-crystallin domain, increases oligomeric size, and modestly increases chaperone activity. Our results suggest a conserved mechanism of pH-dependent structural regulation among the human sHSPs that possess the conserved histidine, although the functional consequences of the structural modulations vary for different sHSPs.

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Section: Discussioncontrasting

confidence: 69%

pH-dependent structural modulation is conserved in the human small heat shock protein HSBP1

Clouser

Klevit

2017

Cell Stress and Chaperones

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“…At least one Cu 2+ -binding site with picomolar affinity in the α-crystallin domain of αB-crystallin has been demonstrated [195]. NMR spectroscopic study showed that potential ligands coordinating Cu 2+ were present in the loop regions connecting the β3 and β4 strands, and the β5 and β6 + β7 strands, and involved residues His83, His104, His111, and Asp109 [196]. These residues are well conserved among different metazoans as well as in human A-crystallin, Hsp20 and Hsp27 [195].…”

Section: Shsps and Metal Ions Interactionsmentioning

confidence: 99%

“…Our recent study demonstrates that human Hsp27 also binds Cu 2+ with close to picomolar affinity, inhibits the Cu 2+ -ascorbate induced generation of ROS and confers cytoprotection [196]. Treating the human neuroblastoma cell line, IMR-32, with Cu 2+ leads to up-regulation of endogenous Hsp27, and over expression of Hsp27 in these cells protects them from Cu 2+ -induced cell death [196]. homeostasis conditions [191,194,196].…”

Section: Shsps and Metal Ions Interactionsmentioning

confidence: 99%

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Small heat shock proteins: Role in cellular functions and pathology

Raman

Tangirala

Rao

2015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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386

321

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Small heat shock proteins (sHsps) are conserved across species and are important in stress tolerance. Many sHsps exhibit chaperone-like activity in preventing aggregation of target proteins, keeping them in a folding-competent state and refolding them by themselves or in concert with other ATP-dependent chaperones. Mutations in human sHsps result in myopathies, neuropathies and cataract. Their expression is modulated in diseases such as Alzheimer's, Parkinson's and cancer. Their ability to bind Cu2+, and suppress generation of reactive oxygen species (ROS) may have implications in Cu2+-homeostasis and neurodegenerative diseases. Circulating αB-crystallin and Hsp27 in the plasma may exhibit immunomodulatory and anti-inflammatory functions. αB-crystallin and Hsp20 exhitbit anti-platelet aggregation: these beneficial effects indicate their use as potential therapeutic agents. sHsps have roles in differentiation, proteasomal degradation, autophagy and development. sHsps exhibit a robust anti-apoptotic property, involving several stages of mitochondrial-mediated, extrinsic apoptotic as well as pro-survival pathways. Dynamic N- and C-termini and oligomeric assemblies of αB-crystallin and Hsp27 are important factors for their functions. We propose a "dynamic partitioning hypothesis" for the promiscuous interactions and pleotropic functions exhibited by sHsps. Stress tolerance and anti-apoptotic properties of sHsps have both beneficial and deleterious consequences in human health and diseases. Conditional and targeted modulation of their expression and/or activity could be used as strategies in treating several human disorders. The review attempts to provide a critical overview of sHsps and their divergent roles in cellular processes particularly in the context of human health and disease.

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“…Under physiological conditions, copper can catalyze ROS formation via Fentonlike reaction . Disruptions in copper homeostasis are responsible for the neurological symptoms, such as PD (Tisato et al 2010;Asthana et al 2014). Some studies have indicated that longterm exposure ([20 years) to copper increases the risk of PD (Gorell et al 1999).…”

Section: Coppermentioning

confidence: 99%

The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms

et al. 2016

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Parkinson's disease (PD) is the second most common neurodegenerative disease with gradual loss of dopaminergic neurons. Despite extensive research in the past decades, the etiology of PD remains elusive. Nevertheless, multiple lines of evidence suggest that oxidative stress is one of the common causes in the pathogenesis of PD. It has also been suggested that heavy metal-associated oxidative stress may be implicated in the etiology and pathogenesis of PD. Here we review the roles of redox metals, including iron, copper and cobalt, in PD. Iron is a highly reactive element and deregulation of iron homeostasis is accompanied by concomitant oxidation processes in PD. Copper is a key metal in cell division process, and it has been shown to have an important role in neurodegenerative diseases such as PD. Cobalt induces the generation of reactive oxygen species (ROS) and DNA damage in brain tissues.

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Hsp27 suppresses the Cu2+-induced amyloidogenicity, redox activity, and cytotoxicity of α-synuclein by metal ion stripping

Cited by 16 publications

References 62 publications

pH-dependent structural modulation is conserved in the human small heat shock protein HSBP1

pH-dependent structural modulation is conserved in the human small heat shock protein HSBP1

Small heat shock proteins: Role in cellular functions and pathology

The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms

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