HSP40 proteins use class-specific regulation to drive HSP70 functional diversity

Faust, Ofrah; Abayev-Avraham, Meital; Wentink, Anne S.; Maurer, Michael; Nillegoda, Nadinath B.; London, Nir; Bukau, Bernd; Rosenzweig, Rina

doi:10.1038/s41586-020-2906-4

Cited by 159 publications

(261 citation statements)

References 59 publications

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“…While the inherent ATPase activity of human Hsp70 is significantly slow, it is stimulated by the Hsp40/DNAJ family upon interaction with the J-domain, which additionally aids Hsp70 in the selective recruitment of clients [24,27,31]. Hsp40/DNAJ proteins interact differently with Hsp70 chaperones [28]. In the major class B, DNAJB1 exhibits a class-dependent autoinhibitory mechanism, in which a Gly/Phe-rich segment blocks the Hsp70-binding sites located in the J-domain.…”

Section: Dynamic Hsp70 and Hsp90 Are Closely Monitored By Co-chaperonesmentioning

confidence: 99%

“…In the major class B, DNAJB1 exhibits a class-dependent autoinhibitory mechanism, in which a Gly/Phe-rich segment blocks the Hsp70-binding sites located in the J-domain. The presence of an additional Hsp70-binding site, which is not present in the class A Hsp40s, releases the Gly-Phe inhibition upon binding to the C-terminal IEEVD tail of Hsp70 [28]. In Hsp70, the NBD and SBD domains are separated by a highly conserved, dynamic, and amphipathic linker, which is crucial for the allosteric communication between both domains [24,32,33].…”

Section: Dynamic Hsp70 and Hsp90 Are Closely Monitored By Co-chaperonesmentioning

confidence: 99%

“…As part of the PN, molecular chaperones not only interfere with early nucleation and amyloid elongation processes but also disassemble already existing pathological amyloids [5]. The Hsp70 disaggregation machinery (composed of Hsp70, Hsp40, and Hsp110-type nucleotide exchange factors; Figure 1) has the capacity to disassemble in vitro preformed amyloids of tau [154], α-synuclein [28,[155][156][157], and HTT [55] with varying efficiencies. Furthermore, tau amyloid extracted from human Alzheimer's brain tissue was disassembled by Hsp70, demonstrating that this disaggregation machinery is able to dissociate disease-relevant species [154].…”

Section: Interplay Between Chaperones and Amyloidsmentioning

confidence: 99%

“…Hsp110 potentiates α-synuclein amyloid disaggregation, acting together with DNAJB1 loading Hsp70 proteins in a densely packed arrangement at the aggregate surface, which is key for the generation of entropic-pulling forces that destabilize the amyloid fold [157,168,169]. In this process, the aforementioned DNAJB1 Gly-Phe auto-inhibition is key for efficient targeting and clustering of Hsp70 onto the surface of an α-synuclein amyloid [28]. While Hsp110 is key for aggregate disassembly, the Hsp40 family member availability drives the aggregate specificity [28,157,170].…”

Section: Interplay Between Chaperones and Amyloidsmentioning

confidence: 99%

“…Client recognition specificity is modulated by a large array of co-chaperones ( Figure 1). Hsp70 is mainly regulated by the versatile family of Hsp40/DNAJ chaperones [24,27,28] and assisted by sHsps [20], whereas Hsp90 associates with a large cohort of co-chaperones [22,29,30]. In short, Hsp70, Hsp90, and their co-chaperones are crucial members of the PN that are able to recognize misfolded proteins, aberrant condensates and protein aggregates, triaging proteins for refolding or degradation [2].…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

Hervás

Oroz

2020

IJMS

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Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

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Section: Dynamic Hsp70 and Hsp90 Are Closely Monitored By Co-chaperonesmentioning

confidence: 99%

Section: Dynamic Hsp70 and Hsp90 Are Closely Monitored By Co-chaperonesmentioning

confidence: 99%

Section: Interplay Between Chaperones and Amyloidsmentioning

confidence: 99%

Section: Interplay Between Chaperones and Amyloidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

Hervás

Oroz

2020

IJMS

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Comparative structural and functional analysis of the glycine‐rich regions of Class A and B J‐domain protein cochaperones of Hsp70

Ciesielski,

Schilke,

Stolarska

et al. 2024

FEBS Letters

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J‐domain proteins are critical Hsp70 co‐chaperones. A and B types have a poorly understood glycine‐rich region (Grich) adjacent to their N‐terminal J‐domain (Jdom). We analyzed the ability of Jdom/Grich segments of yeast Class B Sis1 and a suppressor variant of Class A, Ydj1, to rescue the inviability of sis1‐∆. In each, we identified a cluster of Grich residues required for rescue. Both contain conserved hydrophobic and acidic residues and are predicted to form helices. While, as expected, the Sis1 segment docks on its J‐domain, that of Ydj1 does not. However, data suggest both interact with Hsp70. We speculate that the Grich–Hsp70 interaction of Classes A and B J‐domain proteins can fine tune the activity of Hsp70, thus being particularly important for the function of Class B.

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Pseudophosphorylation of single residues of the J‐domain of DNAJA2 regulates the holding/folding balance of the Hsc70 system

Velasco‐Carneros,

Bernardo‐Seisdedos,

Maréchal

et al. 2024

Protein Science

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The Hsp70 system is essential for maintaining protein homeostasis and comprises a central Hsp70 and two accessory proteins that belong to the J‐domain protein (JDP) and nucleotide exchange factor families. Posttranslational modifications offer a means to tune the activity of the system. We explore how phosphorylation of specific residues of the J‐domain of DNAJA2, a class A JDP, regulates Hsc70 activity using biochemical and structural approaches. Among these residues, we find that pseudophosphorylation of Y10 and S51 enhances the holding/folding balance of the Hsp70 system, reducing cochaperone collaboration with Hsc70 while maintaining the holding capacity. Truly phosphorylated J domains corroborate phosphomimetic variant effects. Notably, distinct mechanisms underlie functional impacts of these DNAJA2 variants. Pseudophosphorylation of Y10 induces partial disordering of the J domain, whereas the S51E substitution weakens essential DNAJA2‐Hsc70 interactions without a large structural reorganization of the protein. S51 phosphorylation might be class‐specific, as all cytosolic class A human JDPs harbor a phosphorylatable residue at this position.

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HSP40 proteins use class-specific regulation to drive HSP70 functional diversity

Cited by 159 publications

References 59 publications

Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

Comparative structural and functional analysis of the glycine‐rich regions of Class A and B J‐domain protein cochaperones of Hsp70

Pseudophosphorylation of single residues of the J‐domain of DNAJA2 regulates the holding/folding balance of the Hsc70 system

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