Allosteric Mechanism of the Hsp90 Chaperone Interactions with Cochaperones and Client Proteins by Modulating Communication Spines of Coupled Regulatory Switches: Integrative Atomistic Modeling of Hsp90 Signaling in Dynamic Interaction Networks

2020 ◽  
Vol 60 (7) ◽  
pp. 3616-3631
Author(s):  
Lindy Astl ◽  
Gabrielle Stetz ◽  
Gennady M. Verkhivker
Keyword(s):  
Dynamic Interaction ◽  
Interaction Networks ◽  
Atomistic Modeling ◽  
Allosteric Mechanism ◽  
Hsp90 Chaperone ◽  
Client Proteins ◽  
Chaperone Interactions

Hsp90 Quaternary Structures and the Chaperone Cycle: Highly Flexible Dimeric and Oligomeric Structures and Their Regulation by Co-Chaperones

2018 ◽  
Vol 16 (1) ◽  
pp. 5-11
Author(s):  
Eléonore Lepvrier ◽  
Daniel Thomas ◽  
Cyrille Garnier
Keyword(s):  
Conformational Changes ◽  
Client Protein ◽  
Key Players ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Client Proteins ◽  
Quaternary Structures ◽  
Chaperone Interactions ◽  
High Flexibility ◽  
Future Work

Proposed models of the function of Hsp90 are characterised by high flexibility of the dimeric state and conformational changes regulated by both nucleotide binding and hydrolysis, and by co-chaperone interactions. In addition to its dimeric state, Hsp90 self-associates upon particular stimuli. The Hsp90 dimer is the building block up to the hexamer that we named “cosy nest”, and the dodecamer results from the association of two hexamers. Oligomers exhibit chaperone activity, but their exact mechanism of action has not yet been determined. One of the best ways to elucidate how oligomers might operate is to study their interactions with co-chaperone proteins known to regulate the Hsp90 chaperone cycle, such as p23 and Aha1. In this review, we summarise recent results and conclude that Hsp90 oligomers are key players in the chaperone cycle. Crucible-shaped quaternary structures likely provide an ideal environment for client protein accommodation and folding, as is the case for other Hsp families. Confirmation of the involvement of Hsp90 oligomers in the chaperone cycle and a better understanding of their functionality will allow us to address some of the more enigmatic aspects of Hsp90 activity. Utilising this knowledge, future work will highlight how Hsp90 oligomers and co-chaperones cooperate to build the structures required to fold or refold numerous different client proteins.

Myopathy mutations in DNAJB6 slow conformer specific substrate processing that is rescued by NEF modulation

2021 ◽  
Author(s):  
Ankan K. Bhadra ◽  
Michael J. Rau ◽  
Jil A. Daw ◽  
James A.J. Fitzpatrick ◽  
Conrad C. Weihl ◽  
...  
Keyword(s):  
Chaperone Activity ◽  
Specific Substrate ◽  
Yeast Prion ◽  
Protein Aggregate ◽  
Client Proteins ◽  
Chaperone Interactions ◽  
Chaperone Network ◽  
Shock Proteins ◽  
Substrate Processing

Molecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. In fact, dominant mutations in DNAJB6 (Hsp40/Sis1), an Hsp70 co-chaperone, leads to a protein aggregate myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). DNAJB6 client proteins and co-chaperone interactions in skeletal muscle are not known. Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights, and found that LGMDD1 mutants affect Hsp40 functions. Strikingly, the mutants changed the structure of client protein aggregates, as determined by altered distribution of prion strains. They also impair the Hsp70 ATPase cycle, dimerization, and substrate processing and consequently poison the function of wild-type protein. These results define the mechanisms by which LGMDD1 mutations alter chaperone activity and provide avenues for therapeutic intervention.

scholarly journals Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

2012 ◽  
Vol 17 (3) ◽  
Author(s):  
Eva Ruckova ◽  
Petr Muller ◽  
Rudolf Nenutil ◽  
Borivoj Vojtesek
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Binding Sites ◽  
Patient Survival ◽  
Proliferating Cells ◽  
Response Elements ◽  
Over Expression ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Client Proteins

AbstractActivation of the Hsp90 chaperone system is a characteristic of cancer cells. The regulation of chaperone activities involves their interaction with cochaperones; therefore we investigated the expression of Hsp70 and Hsp90 and their specific co-chaperones HOP and CHIP in cancer cell lines and primary cancers. Inhibition of Hsp90 by 17AAG increased the levels of Hsp70, Hsp90 and HOP but not CHIP mRNA in cancer cells. These changes are linked to activation of the HSF1 transcription factor and we show that the HOP promoter contains HSF1 binding sites, and that HSF1 binding to the HOP promoter is increased following 17AAG. The lack of alteration in the co-chaperone CHIP is explained by a lack of HSF response elements in the CHIP promoter. Non-proliferating cells expressed higher levels of CHIP and lower HOP, Hsp70 and Hsp90 levels compared to proliferating cells. Decreased expression of CHIP in proliferating cancer cells is in keeping with its proposed tumor suppressor properties, while over-expression of HOP in proliferating cells may contribute to excessive Hsp90 activity and stabilization of client proteins in tumors. In a panel of colorectal cancer samples, increased expression of Hsp70 and an increased ratio of HOP to CHIP were found, and were associated with decreased median survival. These data indicate that multiple changes occur in the chaperone/co-chaperone system in cancer that impact patient survival. It is likely that the ability to identify individual alterations to this system will be beneficial for treatment strategy decisions, particularly those that employ chaperone inhibitors.

scholarly journals Dynamic interaction networks in a hierarchically organized tissue

2010 ◽  
Vol 6 (1) ◽  
pp. 417 ◽  
Author(s):  
Daniel C Kirouac ◽  
Caryn Ito ◽  
Elizabeth Csaszar ◽  
Aline Roch ◽  
Mei Yu ◽  
...  
Keyword(s):  
Dynamic Interaction ◽  
Interaction Networks

scholarly journals Structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client-maturation state

2021 ◽  
Author(s):  
Kanghyun Lee ◽  
Aye C. Thwin ◽  
Eric Tse ◽  
Stephanie N. Gates ◽  
Daniel R. Southworth
Keyword(s):  
Prolyl Isomerase ◽  
Ppiase Activity ◽  
Peptidyl Prolyl Isomerase ◽  
Recognition Element ◽  
Middle Domain ◽  
Ppiase Domain ◽  
Hsp90 Chaperone ◽  
Client Proteins ◽  
Maturation State ◽  
Tpr Domain

SummaryThe Hsp90 chaperone promotes the folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during the folding of kinases, nuclear receptors and tau. Here we have determined the cryo-EM structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å that, together with mutagenesis and crosslinking analysis, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent Hsp90 client binding sites, while a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 could thereby act on specific client residues presented during Hsp90-catalyzed remodeling.

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