Fine-tuning of the Hsc70-based Human Protein Disaggregase Machinery by the Distinctive C-terminal Extension of Apg2

Cabrera, Yovana; Bernardo‐Seisdedos, Ganeko; Dublang, Leire; Albesa‐Jové, David; Orozco, Natalia; Viguera, Ana Rosa; Millet, Óscar; Muga, Arturo; Moro, Fernando

doi:10.1016/j.jmb.2022.167841

Cited by 3 publications

(1 citation statement)

References 61 publications

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“…To prove it, we first demonstrated that the difference in the disaggregating/refolding activity between the S51 variants was also observed using aggregates of glucose‐6‐phosphate dehydrogenase (G6PDH), indicating that it was substrate‐independent (Figure 3b , right panel). Then, the ability of wt DNAJA2 and its two protein variants to interact with G6PDH aggregates, and to recruit Hsc70 was analyzed in the presence of Apg2, which favors chaperone transfer to the aggregate surface (Cabrera et al, 2022 ). Both DNAJA2 variants interacted with G6PDH aggregates similarly to the wt protein, but DNAJA2‐S51E recruited two‐fold less Hsc70 than wt DNAJA2 (Figure 3c,d ).…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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Broken but not beaten: Challenge of reducing the amyloids pathogenicity by degradation

Sulatsky,

Stepanenko,

Stepanenko

et al. 2024

Journal of Advanced Research

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HSPA4 Enhances BRSV Entry via Clathrin-Mediated Endocytosis Through Regulating the PI3K–Akt Signaling Pathway and ATPase Activity of HSC70

Liu,

Li,

Shao

et al. 2024

Viruses

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Bovine respiratory syncytial virus (BRSV) is an enveloped RNA virus that utilizes clathrin-mediated endocytosis for cell entry and is a significant pathogen in bovine respiratory disease (BRD). Heat shock protein family A member 4 (HSPA4), a member of the HSP70 family, is known to be involved in the progression of various cancers. However, its role in virus entry has not been previously explored. Through experiments involving Western blot analysis, virus titer, and virus copies analysis, we demonstrated that HSPA4 can regulate BRSV entry and replication. The specific regulation mode is to enhance BRSV entry by promoting clathrin-mediated endocytosis. We used Western blot, virus titer, virus copies analysis, and IFA to demonstrate that HSPA4 can promote clathrin heavy chain protein (CHC) expression and further promote BRSV entry by activating the PI3K–Akt signaling pathway. Furthermore, we observed that HSPA4 boosts the efficiency of clathrin-mediated endocytosis by increasing the ATPase activity of heat shock cognate protein 70 (HSC70), thereby facilitating BRSV entry. Additionally, our investigation into the impact of HSPA4 on the entry of other viruses revealed that HSPA4 can facilitate the entry of a variety of viruses into host cells.

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Fine-tuning of the Hsc70-based Human Protein Disaggregase Machinery by the Distinctive C-terminal Extension of Apg2

Cited by 3 publications

References 61 publications

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

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

Broken but not beaten: Challenge of reducing the amyloids pathogenicity by degradation

HSPA4 Enhances BRSV Entry via Clathrin-Mediated Endocytosis Through Regulating the PI3K–Akt Signaling Pathway and ATPase Activity of HSC70

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