Chaperone‐like activity of the N‐terminal region of a human small heat shock protein and chaperone‐functionalized nanoparticles

Gliniewicz, Emily F.; Chambers, Kelly M.; Leon, Elizabeth R. De; Sibai, Diana; Campbell, Helen C.; McMenimen, Kathryn A.

doi:10.1002/prot.25662

Cited by 3 publications

(3 citation statements)

References 74 publications

(176 reference statements)

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“…The mechanism of the sHsp chaperone function has been challenging to untangle due to their dynamic structure heterogeneity [ 38 , 90 ]. sHsps have a characterized structure that spans from monomers, dimers, and small oligomers up to large heterogeneous oligomers, and in vitro chaperone activity has been observed across all structural conformations [ 24 , 27 , 54 , 91 , 92 ]. Structural and functional studies have suggested that sHsp dimers may be the most active chaperone species; however, unraveling the complexity between structure and function for substrates remains challenging [ 1 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies of the truncated species have suggested that substrate-binding occurs within the ACD domain. However, evidence also points toward a physiological role for the N-terminal extension and possibly all three domains in retaining in vivo activity [ 10 , 25 , 26 , 27 , 28 ]. It is likely that each domain facilitates sHsp–substrate interactions.…”

Section: Introductionmentioning

confidence: 99%

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HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

Wang,

Teng,

Liu

et al. 2023

IJMS

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Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that function as “holdases” and prevent protein aggregation due to changes in temperature, pH, or oxidation state. sHsps have a conserved α-crystallin domain (ACD), which forms the dimer building block, flanked by variable N- and C-terminal regions. sHsps populate various oligomeric states as a function of their sequestrase activity, and these dynamic structural features allow the proteins to interact with a plethora of cellular substrates. However, the molecular mechanisms of their dynamic conformational assembly and the interactions with various substrates remains unclear. Therefore, it is important to gain insight into the underlying physicochemical properties that influence sHsp structure in an effort to understand their mechanism(s) of action. We evaluated several disease-relevant mutations, D109A, F113Y, R116C, R120G, and R120C, in the ACD of HspB5 for changes to in vitro chaperone activity relative to that of wildtype. Structural characteristics were also evaluated by ANS fluorescence and CD spectroscopy. Our results indicated that mutation Y113F is an efficient holdase, while D109A and R120G, which are found in patients with myofibrillar myopathy and cataracts, respectively, exhibit a large reduction in holdase activity in a chaperone-like light-scattering assay, which indicated alterations in substrate–sHsp interactions. The extent of the reductions in chaperone activities are different among the mutants and specific to the substrate protein, suggesting that while sHsps are able to interact with many substrates, specific interactions provide selectivity for some substrates compared to others. This work is consistent with a model for chaperone activity where key electrostatic interactions in the sHsp dimer provide structural stability and influence both higher-order sHsp interactions and facilitate interactions with substrate proteins that define chaperone holdase activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

Wang,

Teng,

Liu

et al. 2023

IJMS

Self Cite

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“…Previous studies showed that C-terminal inhibitors inhibit the anti-aggregation function of C-terminus of Hsp90α ( Allan et al ., 2006 ). Determining anti-aggregation function is a standard method used to evaluate the chaperone-like activity of a protein ( Gliniewicz et al ., 2019 ). Our results indicate that Chaetocin has the ability to inhibit the chaperone function of Hsp90, consolidating that Chaetocin binds to C-terminus of Hsp90, and is a new kind of C-terminal inhibitor of Hsp90.…”

Section: Discussionmentioning

confidence: 99%

SUV39H1 is a New Client Protein of Hsp90 Degradated by Chaetocin as a Novel C-Terminal Inhibitor of Hsp90

Lian

Lin

Tang

et al. 2021

Biomolecules & Therapeutics

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Hsp90 is often overexpressed with activated form in cancer cells, and many key cellular proteins are dependent upon the Hsp90 machinery (these proteins are called “client protein”). Nowadays, more client proteins and more inhibitors of Hsp90 are being discovered. Chaetocin has been identified as an inhibitor of histone methyl transferase SUV39H1. Herein, we find that Chaetocin is an inhibitor of Hsp90 which binds to the C-terminal of Hsp90α. Chaetocin inhibited a variety of Hsp90 client proteins including AMl1-ETO and BCL-ABL, the mutant fusion-protein in the K562 and HL-60 cells. SUV39H1 mediates epigenetic events in the pathophysiology of hematopoietic disorders. We found that inhibition of Hsp90 by Chaetocin and 17-AAG had ability to induce degradation of SUV39H1 through proteasome pathway. In addition, SUV39H1 interacted with Hsp90 through co-chaperone HOP. These results suggest that SUV39H1 belongs to a client protein of Hsp90. Moreover, Chaetocin was able to induce cell differentiation in the two cells in the concentration range of Hsp90 inhibition. Altogether, our results demonstrate that SUV39H1 is a new client protein of Hsp90 degradated by Chaetocin as a novel C-terminal inhibitor of Hsp90. The study establishes a new relationship of Chaetocin and SUV39H1, and paves an avenue for exploring a new strategy to target SUV39H1 by inhibition of Hsp90 in leukemia.

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Emerging therapeutic roles of small heat shock protein-derived mini-chaperones and their delivery strategies

Reddy

2023

Biochimie

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Chaperone‐like activity of the N‐terminal region of a human small heat shock protein and chaperone‐functionalized nanoparticles

Cited by 3 publications

References 74 publications

HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

HspB5 Chaperone Structure and Activity Are Modulated by Chemical-Scale Interactions in the ACD Dimer Interface

SUV39H1 is a New Client Protein of Hsp90 Degradated by Chaetocin as a Novel C-Terminal Inhibitor of Hsp90

Emerging therapeutic roles of small heat shock protein-derived mini-chaperones and their delivery strategies

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