Nucleotide Exchange Factors for Hsp70 Chaperones

Rampelt, Heike; Mayer, Matthias P.; Bukau, Bernd

doi:10.1007/978-1-4939-7477-1_13

Cited by 9 publications

(5 citation statements)

References 37 publications

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“…Nucleotide exchange factors (NEFs), such as Hsp110, stimulate the release of substrate from ADP-bound Hsp72, by facilitating the re-binding of ATP (31) To test the effect of NEF, we performed the ATP mediated substrate release experiment in the presence of Hsp110 and unlabeled substrate peptide (Fig. 3F).…”

Section: Resultsmentioning

confidence: 99%

Mitotic phosphorylation regulates Hsp72 spindle localization by uncoupling ATP binding from substrate release

et al. 2018

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Hsp72 is a member of the 70-kDa heat shock family of molecular chaperones (Hsp70s) that comprise a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD) connected by a linker that couples the exchange of adenosine diphosphate (ADP) for adenosine triphosphate (ATP) with the release of the protein substrate. Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation. We determined the crystal structure of the Hsp72 NBD containing a genetically encoded phosphoserine at position 66. This revealed structural changes that stabilized interactions between subdomains within the NBD. ATP binding to the NBD of unmodified Hsp72 resulted in the release of substrate from the SBD, but phosphorylated Hsp72 retained substrate in the presence of ATP. Mutations that prevented phosphorylation-dependent subdomain interactions restored the connection between ATP binding and substrate release. Thus, phosphorylation of Thr is a reversible mechanism that decouples the allosteric connection between nucleotide binding and substrate release, providing further insight into the regulation of the Hsp70 family. We propose that phosphorylation of Hsp72 on Thr by NEK6 during mitosis promotes its localization to the spindle by stabilizing its interactions with components of the mitotic spindle.

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Section: Resultsmentioning

confidence: 99%

Mitotic phosphorylation regulates Hsp72 spindle localization by uncoupling ATP binding from substrate release

et al. 2018

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“…ATP hydrolysis also drives the dissociation of the J-domain of JDP from ADP-bound Hsp70, for which it has low affinity. Another class of cochaperones, the nucleotide exchange factors (NEFs), facilitate client dissociation from Hsp70 by accelerating ADP release and, in some cases, directly contacting the Hsp70-SBD to drive client displacement ( Figure 1 A) [ 13 , 14 , 15 , 16 ]. These allosteric regulations allow Hsp70 to act as molecular machines that capture and protect unfolded segments on client proteins and, after some dwell time set by the ATPase cycle, to release client proteins in conformations that are more conducive to folding ( Figure 1 B, steps 2–3) [ 17 , 18 ].…”

Section: Hsp70: An Allosteric Machine With Diverse Functions In Prote...mentioning

confidence: 99%

Role of Hsp70 in Post-Translational Protein Targeting: Tail-Anchored Membrane Proteins and Beyond

Shan

2023

IJMS

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The Hsp70 family of molecular chaperones acts as a central ‘hub’ in the cell that interacts with numerous newly synthesized proteins to assist in their biogenesis. Apart from its central and well-established role in facilitating protein folding, Hsp70s also act as key decision points in the cellular chaperone network that direct client proteins to distinct biogenesis and quality control pathways. In this paper, we review accumulating data that illustrate a new branch in the Hsp70 network: the post-translational targeting of nascent membrane and organellar proteins to diverse cellular organelles. Work in multiple pathways suggests that Hsp70, via its ability to interact with components of protein targeting and translocation machineries, can initiate elaborate substrate relays in a sophisticated cascade of chaperones, cochaperones, and receptor proteins, and thus provide a mechanism to safeguard and deliver nascent membrane proteins to the correct cellular membrane. We discuss the mechanistic principles gleaned from better-studied Hsp70-dependent targeting pathways and outline the observations and outstanding questions in less well-studied systems.

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“…The pharmacological inhibition of Hsp90 resulted in up‐regulation of Hsp70 and Hsp40, which could control the expression of several synaptic proteins but could also drive the misfolded protein to proteasome degradation (33–36). Another chaperone involved is Hsp110, which interacts with Hsp70 and increases its ATPase activity (37, 38). Hsp110 is known to suppress the aggregation and folding of proteins and to protect them from the adverse effects of various stresses.…”

Section: Hsp Expression At the Bbb Levelmentioning

confidence: 99%

Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection?

Thüringer

Garrido

2019

The FASEB Journal

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Brain microvascular endothelial cells (BMECs) interact with astrocytes and pericytes to form the blood–brain barrier (BBB). Their compromised function alters the BBB integrity, which is associated with early events in the pathogenesis of cancer, neurodegenerative diseases, and epilepsy. Interestingly, these conditions also induce the expression of heat shock proteins (HSPs). Here we review the contribution of major HSP families to BMEC and BBB function. Although investigators mainly report protective effects of HSPs in brain, contrasted results were obtained in BMEC, which depend both on the HSP and on its location, intra‐ or extracellular. The therapeutic potential of HSPs must be scrupulously analyzed before targeting them in patients to reduce the progression of brain lesions and improve neurologic outcomes in the long term.—Thuringer, D., Garrido, C. Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection? FASEB J. 33, 11629–11639 (2019). http://www.fasebj.org

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Nucleotide Exchange Factors for Hsp70 Chaperones

Cited by 9 publications

References 37 publications

Mitotic phosphorylation regulates Hsp72 spindle localization by uncoupling ATP binding from substrate release

Mitotic phosphorylation regulates Hsp72 spindle localization by uncoupling ATP binding from substrate release

Role of Hsp70 in Post-Translational Protein Targeting: Tail-Anchored Membrane Proteins and Beyond

Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection?

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