Interaction of Hsp70 chaperones with substrates

Rüdiger, Stefan; Buchberger, Alexander; Bukau, Bernd

doi:10.1038/nsb0597-342

Cited by 345 publications

(302 citation statements)

References 71 publications

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“…S1. It is of interest that many of the consensus motifs are enriched in hydrophobic residues (Leu, Ile, Val, Phe, and Tyr), which are often found in Hsp70 substrates (38). Importantly, we found that the location of consensus motifs within M-domain helix 2 (motifs E and F) overlapped with mutation sites in Escherichia coli ClpB, which either impaired ClpB's innate protein disaggregating activity or affected the functional cooperation between ClpB and DnaK/DnaJ/GrpE in substrate recovery (34).…”

Section: Resultsmentioning

confidence: 99%

Heat shock protein (Hsp) 70 is an activator of the Hsp104 motor

Lee¹,

Kim²,

Biter³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

111

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Heat shock protein (Hsp) 104 is a ring-forming, protein-remodeling machine that harnesses the energy of ATP binding and hydrolysis to drive protein disaggregation. Although Hsp104 is an active ATPase, the recovery of functional protein requires the speciesspecific cooperation of the Hsp70 system. However, like Hsp104, Hsp70 is an active ATPase, which recognizes aggregated and aggregation-prone proteins, making it difficult to differentiate the mechanistic roles of Hsp104 and Hsp70 during protein disaggregation. Mapping the Hsp70-binding sites in yeast Hsp104 using peptide array technology and photo-cross-linking revealed a striking conservation of the primary Hsp70-binding motifs on the Hsp104 middle-domain across species, despite lack of sequence identity. Remarkably, inserting a Strep-Tactin binding motif at the spatially conserved Hsp70-binding site elicits the Hsp104 protein disaggregating activity that now depends on Strep-Tactin but no longer requires Hsp70/40. Consistent with a Strep-Tactin-dependent activation step, we found that full-length Hsp70 on its own could activate the Hsp104 hexamer by promoting intersubunit coordination, suggesting that Hsp70 is an activator of the Hsp104 motor.ClpB | DnaK | Hsp100 | molecular chaperone

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Section: Resultsmentioning

confidence: 99%

Heat shock protein (Hsp) 70 is an activator of the Hsp104 motor

Lee¹,

Kim²,

Biter³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

111

View full text Add to dashboard Cite

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“…Moreover, BAG6 and HSP70 seem to compete for substrate binding as BAG6 could prevent HSP70-mediated refolding of denatured luciferase in an in vitro assay (Wang et al, 2011). Although BAG6 preferably binds to longer hydrophobic patches (Mariappan et al, 2010) and HSP70/HSP90 to shorter hydrophobic patches (Jackson, 2013;Rudiger et al, 1997) considerable overlap in both systems is likely. Definition of the potential proportion of antigen that is handled by BAG6 would therefore be possible if BAG6-mediated degradation could be inhibited after substrate binding to the chaperone.…”

Section: Discussionmentioning

confidence: 99%

Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bitzer

Basler

Groettrup

2016

Molecular Immunology

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a b s t r a c tAntigen processing for direct presentation on MHC class I molecules is a multistep process requiring the concerted activity of several cellular complexes. The essential steps at the beginning of this pathway, namely protein synthesis at the ribosome and degradation via the proteasome, have been known for years. Nevertheless, there is a considerable lack of factors identified to function between protein synthesis and degradation during antigen processing. Here, we analyzed the impact of the chaperone BAG6 on MHC class I cell surface expression and presentation of virus-derived peptides. Although an essential role of BAG6 in antigen processing has been proposed previously, we found BAG6 to be dispensable in this pathway. Still, interaction of BAG6 and the model antigen tyrosinase was enhanced during proteasome inhibition pointing towards a role of BAG6 in antigen degradation. Redundant chaperone pathways potentially mask the contribution of BAG6 to antigen processing and presentation.

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“…An attractive feature of the unfolding/threading model of Hsp104 function is, rather than partially folded, partially aggregated proteins that are expected to be produced by a crowbar mechanism, the end product of the disaggregase would be extended polypeptide chains that are ideal substrates for Hsp70 binding (37). Although it is conceivable that the disaggregase and refolding components of the bichaperone network function entirely independently, a physical association between the components is an appealing notion.…”

Section: Discussionmentioning

confidence: 99%