J-domain Proteins form Binary Complexes with Hsp90 and Ternary Complexes with Hsp90 and Hsp70

Wickramaratne, Anushka; Liao, Jui‐Yun Rei; Doyle, Shannon M.; Hoskins, Joel R.; Puller, Gabrielle C; Scott, Madison; Alao, John Paul; Obaseki, Ikponwmosa; Dinan, Jerry C.; Maity, Tapan K.; Jenkins, Lisa M. Miller; Kravats, Andrea N.; Wickner, Sue

doi:10.1016/j.jmb.2023.168184

Cited by 7 publications

(4 citation statements)

References 55 publications

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“…Although J‐proteins all contain a conserved J‐domain, they have evolved from fusion or truncation of other subdomains over time, which creates a large variation in the sequence and functions of CTDs [1,51] . Unlike Mtb, E. coli contains five J‐domain proteins that do not all belong to class A and appear to have different cellular functions [52–53] . In some eukaryotic J‐proteins, other subdomains are known to form not only intermolecular contacts with Hsp70s, but intramolecular contacts with the J‐domain.…”

Section: Discussionmentioning

confidence: 99%

“…[1,51] Unlike Mtb, E. coli contains five J-domain proteins that do not all belong to class A and appear to have different cellular functions. [52][53] In some eukaryotic J-proteins, other subdomains are known to form not only intermolecular contacts with Hsp70s, but intramolecular contacts with the J-domain. In the yeast J-protein, Sis1, a salt bridge forms between a Glu in the Jdomain and an Arg in the G/F linker.…”

Section: Discussionmentioning

confidence: 99%

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Bacterial J‐Domains with C‐Terminal Tags Contact the Substrate Binding Domain of DnaK and Sequester Chaperone Activity

Nelson,

Soper,

Lupoli

2023

ChemBioChem

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Functional interactions between the molecular chaperone DnaK with cofactor J‐proteins (DnaJs), and their homologs, are crucial to the maintenance of proteostasis across cell types. In the bacterial pathogen Mycobacterium tuberculosis, DnaK‐DnaJ interactions are essential for cell growth and represent potential targets for antibiotic or adjuvant development. While the N‐terminal J‐domains of J‐proteins are known to form important contacts with DnaK, C‐terminal domains have varied roles. Here, we study the effect of adding C‐terminal tags to N‐terminal J‐domain truncations of mycobacterial DnaJ1 and DnaJ2 to promote additional interactions with DnaK. We find that His6 tags uniquely promote binding to additional sites in the substrate binding domain on the C‐terminus of DnaK. Other C‐terminal tags attached to J‐domains, even peptides known to interact with DnaK, do not produce the same effects. Expression of C‐terminal‐modified DnaJ1 or DnaJ2 J‐domains in mycobacterial cells leads to suppression of chaperone activity following proteotoxic stress, which is exaggerated in the presence of a small molecule DnaK inhibitor. Hence, this work uncovers genetically‐encodable J‐protein variants that may be used to study chaperone‐cofactor interactions in other organisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bacterial J‐Domains with C‐Terminal Tags Contact the Substrate Binding Domain of DnaK and Sequester Chaperone Activity

Nelson,

Soper,

Lupoli

2023

ChemBioChem

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“…The interaction is conserved in both bacteria and yeast, and it is thought to be a mechanism of client transfer during protein remodeling. 38 …”

Section: Toward Inhibitors Of Heat Shock Proteins As Therapeuticsmentioning

confidence: 99%

Stress biology: Complexity and multifariousness in health and disease

Mayer,

Blair,

Blatch

et al. 2024

Cell Stress and Chaperones

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“…The heat shock protein 90 (HSP90) plays an important role in protein maturation, stabilisation, and activation ( Wickramaratne et al, 2023 ). A triterpenoid compound 2-amino-5-chloro-N, 3-dimethylbenzamide (CDDO) was identified by Wu et al It inhibits HSP90, which in turn inhibits GPX4 degradation and lipid peroxidation, and downregulates ROS, protecting cells from damage caused byferroptosis ( Wu et al, 2019 ).…”

Section: Small Molecule Ferroptosis Inhibitorsmentioning

confidence: 99%

Ferroptosis inhibitors: past, present and future

Zhang,

Luo,

Xiang

et al. 2024

Front. Pharmacol.

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Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

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J-domain Proteins form Binary Complexes with Hsp90 and Ternary Complexes with Hsp90 and Hsp70

Cited by 7 publications

References 55 publications

Bacterial J‐Domains with C‐Terminal Tags Contact the Substrate Binding Domain of DnaK and Sequester Chaperone Activity

Bacterial J‐Domains with C‐Terminal Tags Contact the Substrate Binding Domain of DnaK and Sequester Chaperone Activity

Stress biology: Complexity and multifariousness in health and disease

Ferroptosis inhibitors: past, present and future

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