Regulation of Human Hsc70 ATPase and Chaperone Activities by Apg2: Role of the Acidic Subdomain

Cabrera, Yovana; Dublang, Leire; Fernández-Higuero, José Ángel; Albesa‐Jové, David; Lucas, María; Viguera, Ana Rosa; Guerin, Marcelo E.; Vilar, José M. G.; Muga, Arturo; Moro, Fernando

doi:10.1016/j.jmb.2018.11.026

Cited by 16 publications

(26 citation statements)

References 69 publications

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“…In vitro this acidic domain stimulates the release of Hsp110s from Hsp70 (i.e. HSPA8) and influences the ATPase cycle of Hsp70 (64). Interestingly, there are differences in the predicted disorder between the acidic loops of Hsp110s.…”

Section: Discussionmentioning

confidence: 99%

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Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

Serlidaki

Rohland

Wentink

et al. 2020

Journal of Biological Chemistry

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Heat shock protein 70 (HSP70) chaperones play a central role in protein quality control and are crucial for many cellular processes, including protein folding, degradation, and disaggregation. Human HSP70s compose a family of 13 members that carry out their functions with the aid of even larger families of co-chaperones. A delicate interplay between HSP70s and co-chaperone recruitment is thought to determine substrate fate, yet it has been generally assumed that all Hsp70 paralogs have similar activities and are largely functionally redundant. However, here we found that when expressed in human cells, two highly homologous HSP70s, HSPA1A and HSPA1L, have opposing effects on cellular handling of various substrates. For example, HSPA1A reduced aggregation of the amyotrophic lateral sclerosis–associated protein variant superoxide dismutase 1 (SOD1)–A4V, whereas HSPA1L enhanced its aggregation. Intriguingly, variations in the substrate-binding domain of these HSP70s did not play a role in this difference. Instead, we observed that substrate fate is determined by differential interactions of the HSP70s with co-chaperones. Whereas most co-chaperones bound equally well to these two HSP70s, Hsp70/Hsp90-organizing protein (HOP) preferentially bound to HSPA1L, and the Hsp110 nucleotide-exchange factor HSPH2 preferred HSPA1A. The role of HSPH2 was especially crucial for the HSPA1A-mediated reduction in SOD1-A4V aggregation. These findings reveal a remarkable functional diversity at the level of the cellular HSP70s and indicate that this diversity is defined by their affinities for specific co-chaperones such as HSPH2.

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Section: Discussionmentioning

confidence: 99%

“…Human Hsp110 have approximately 60% sequence identity ( Figure S6 and Table S2), which could allow for such a functional variability. The binding between Hsp70 and Hsp110 is regulated by an acidic intrinsically disordered domain in Hsp110s (64). In vitro this acidic domain stimulates the release of Hsp110s from Hsp70 (i.e.…”

Section: Discussionmentioning

confidence: 99%

Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

Serlidaki

Rohland

Wentink

et al. 2020

Journal of Biological Chemistry

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“…Although HSC70 often appears as an artifact in MS assays ( 29 ), we did not find HSC70 among proteins pulled down with the Scr control peptide. P155 did not bind to the general peptide-binding region, namely, the SBD domain of HSC70, but selectively bound to the ATPase region of HSC70 and suppressed the ATPase activity of full-length HSC70, which is critical for the HSC70-mediated chaperon cycle of peptide transportation ( 30 ). Given that HSC70 is central for antigen trafficking in DCs, we found that P155 modulated lysosomal localization of antigens and subsequent antigen presentation by MHC class II to CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation

et al. 2020

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Many annotated long noncoding RNAs (lncRNAs) harbor predicted short open reading frames (sORFs), but the coding capacities of these sORFs and the functions of the resulting micropeptides remain elusive. Here, we report that human lncRNA MIR155HG encodes a 17–amino acid micropeptide, which we termed miPEP155 (P155). MIR155HG is highly expressed by inflamed antigen-presenting cells, leading to the discovery that P155 interacts with the adenosine 5′-triphosphate binding domain of heat shock cognate protein 70 (HSC70), a chaperone required for antigen trafficking and presentation in dendritic cells (DCs). P155 modulates major histocompatibility complex class II–mediated antigen presentation and T cell priming by disrupting the HSC70-HSP90 machinery. Exogenously injected P155 improves two classical mouse models of DC-driven auto inflammation. Collectively, we demonstrate the endogenous existence of a micropeptide encoded by a transcript annotated as “non-protein coding” and characterize a micropeptide as a regulator of antigen presentation and a suppressor of inflammatory diseases.

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“…Hsp110s are larger proteins due to the insertion of a proline-rich acidic subdomain (AS) in the β-sandwich of the SBD, and an extension of the intrinsically disordered C-terminal segment [21]. The AS is involved in the interaction with Hsp70 and in the regulation of its ATPase/conformational cycle [61], and both the AS and the C-terminal domain participate in the correct intracellular localization of the isoforms α and β of Hsp105 [62,63]. Although Hsp110s exhibit ATPase activity, they lack the Hsp70-like allosteric docking/undocking of NBD and SBD coupled to ATP binding and hydrolysis, displaying limited conformational changes [64,65,66].…”

Section: Molecular Chaperones Involved In Protein Folding and Protmentioning

confidence: 99%

“…Solubilization of polypeptide chains depends upon the interaction of the chaperones with the aggregate, which is most likely the rate limiting step of the reactivation reaction, as protein aggregate solubilization correlates with refolding of the extracted unfolded molecules [61,81,82]. Similar to the bacterial system, the initial binding of DnaJB1 to the aggregate surface efficiently recruits Hsc70 [61,83]. Apg2 further increases binding of Hsc70 in agreement with the refolding stimulation provided by Hsp110 [25,26,61].…”

Section: Interaction Of Chaperones With Substrate Proteins and Promentioning

confidence: 99%

The Complex Phosphorylation Patterns That Regulate the Activity of Hsp70 and Its Cochaperones

Velasco-Carneros

Dublang

Moro

et al. 2019

IJMS

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Proteins must fold into their native structure and maintain it during their lifespan to display the desired activity. To ensure proper folding and stability, and avoid generation of misfolded conformations that can be potentially cytotoxic, cells synthesize a wide variety of molecular chaperones that assist folding of other proteins and avoid their aggregation, which unfortunately is unavoidable under acute stress conditions. A protein machinery in metazoa, composed of representatives of the Hsp70, Hsp40, and Hsp110 chaperone families, can reactivate protein aggregates. We revised herein the phosphorylation sites found so far in members of these chaperone families and the functional consequences associated with some of them. We also discuss how phosphorylation might regulate the chaperone activity and the interaction of human Hsp70 with its accessory and client proteins. Finally, we present the information that would be necessary to decrypt the effect that post-translational modifications, and especially phosphorylation, could have on the biological activity of the Hsp70 system, known as the “chaperone code”.

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Regulation of Human Hsc70 ATPase and Chaperone Activities by Apg2: Role of the Acidic Subdomain

Cited by 16 publications

References 69 publications

Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation

The Complex Phosphorylation Patterns That Regulate the Activity of Hsp70 and Its Cochaperones

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