The C-terminal region of the human p23 chaperone modulates its structure and function

Seraphim, Thiago Vargas; Gava, Lisandra M.; Mokry, David Z.; Cagliari, Thiago C.; Barbosa, Leandro R.S.; Ramos, Carlos H.I.; Borges, Júlio César

doi:10.1016/j.abb.2014.10.015

Cited by 20 publications

(25 citation statements)

References 46 publications

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“…They also have a positive CD signal at 230 nm, which is a structural sign reported for the hp23 protein . In addition, we used hydrodynamic tools to show that both Lbp23 proteins are elongated monomers in solution, similar to the observations for hp23 . SAXS experiments corroborate these conclusions and indicate that both Lbp23 proteins have sufficiently long dimensions to interact simultaneously with both the N‐ and M‐domains of LbHsp90 .…”

Section: Discussionsupporting

confidence: 76%

Identification of two p23 co‐chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities

et al. 2014

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The small acidic protein called p23 acts as a co-chaperone for heat-shock protein of 90 kDa (Hsp90) during its ATPase cycle. p23 proteins inhibit Hsp90 ATPase activity and show intrinsic chaperone activity. A search for p23 in protozoa, especially trypanosomatids, led us to identify two putative proteins in the Leishmania braziliensis genome that share approximately 30% identity with each other and with the human p23. To understand the presence of two p23 isoforms in trypanosomatids, we obtained the recombinant p23 proteins of L. braziliensis (named Lbp23A and Lbp23B) and performed structural and functional studies. The recombinant proteins share similar solution structures; however, temperature-and chemicalinduced unfolding experiments showed that Lbp23A is more stable than Lbp23B, suggesting that they may have different functions. Lbp23B prevented the temperature-induced aggregation of malic dehydrogenase more efficiently than did Lbp23A, whereas the two proteins had equivalent efficiencies with respect to preventing the temperature-induced aggregation of luciferase. Both proteins interacted with L. braziliensis Hsp90 (LbHsp90) and inhibited its ATPase activity, although their efficiencies differed. In vivo identification studies suggested that both proteins are present in L. braziliensis cells grown under different conditions, although Lbp23B may undergo post-translation modifications. Interaction studies indicated that both Lbp23 proteins interact with LbHsp90. Taken together, our data suggest that the two protozoa p23 isoforms act similarly when regulating Hsp90 function. However, they also have some differences, indicating that the L. braziliensis Hsp90 machine has features providing an opportunity for novel forms of selective inhibition of protozoan Hsp90.

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Section: Discussionsupporting

confidence: 76%

Identification of two p23 co‐chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities

et al. 2014

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“…However, HMS analysis highlighted the major species as being the Hsp90 dimer linked to 3 p23s and a maximum binding stoichiometry of 4 p23s per Hsp90 dimer. This result is in contradiction with previous works showing binding stoichiometries of 1 and 2 p23s per dimer[36,38,39,41,60]. Such stoichiometry is atypical but not aberrant.…”

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confidence: 84%

“…Purified p23 was analyzed by analytical ultracentrifugation and by SEC-MALLS. Velocity analytical ultracentrifugation experiments gave us the sedimentation coefficient at 20°C in water at infinite dilution (s 20,°w ) of 1.9 S (data not shown, Table 1) identical to that determined by [36]. p23 molecular masses of 20.5 kDa and 21.1 kDa were respectively determined by SEC-MALLS and HMS.…”

Section: P23 Is Correctly Foldedmentioning

confidence: 99%

“…We obtained the atypical CD spectrum characteristic of p23 displaying a positive signal at 230 nm [59,60], indicating that the protein was correctly folded. Nevertheless, the obtained CD spectrum was much closer to C-terminal truncated p23 mutants than to the entire protein showed in [36]. To make sure that our p23 did not undergo a Cterminus degradation process, frozen p23 sample was analyzed by ESI-MS. We obtained a mass of 20.73 kDa, which was closed to the average theoretical mass of 20.86 kDa calculated trough amino-acid sequence.…”

Section: P23 Is Correctly Foldedmentioning

confidence: 99%

“…In addition to its intrinsic activity with its own interactome, independent from Hsp90's functions [36,37], the 18.7 kDa p23 globular protein is known to be an Hsp90 ATPase inhibitor [38,39]. Initial studies disagreed about the Hsp90:p23 complex formation: Chadli et al [40] suggested that p23 selectively binds the Hsp90 dimer in its ATPbound state whereas McLaughlin et al suggested that p23 interacts with Hsp90 with and without nucleotides and that the Hsp90 NTD dimerization is not a prerequisite for this association [39].…”

Section: Introductionmentioning

confidence: 99%

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Hsp90 oligomerization process: How can p23 drive the chaperone machineries?

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Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Molecular mechanisms of chaperone‐directed protein folding: Insights from atomistic simulations

Castelli,

Magni,

Bonollo

et al. 2024

Protein Science

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Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved through cycles in which Hsp90 and Hsp70, regulated by task‐specific co‐chaperones, process ATP and become part of a complex network that undergoes extensive compositional and conformational variations. Despite impressive advances in structural knowledge, the mechanisms that regulate the dynamics of functional assemblies, their response to nucleotides, and their relevance for client remodelling are still elusive.Here, we focus on the glucocorticoid receptor (GR):Hsp90:Hsp70:co‐chaperone Hop client‐loading and the GR:Hsp90: co‐chaperone p23 client‐maturation complexes, key assemblies in the folding cycle of glucocorticoid receptor (GR), a client strictly dependent upon Hsp90/Hsp70 for activity.Using a combination of molecular dynamics simulation approaches, we unveil with unprecedented detail the mechanisms that underpin function in these chaperone machineries. Specifically, we dissect the processes by which the nucleotide‐encoded message is relayed to the client and how the distinct partners of the assemblies cooperate to (pre)organize partially‐folded GR during Loading and Maturation. We show how different ligand‐states determine distinct dynamic profiles for the functional interfaces defining the interactions in the complexes and modulate their overall flexibility to facilitate progress along the chaperone‐cycle. Finally, we also show that the GR regions engaged by the chaperone‐machinery display peculiar energetic signatures in the folded state, which enhance the probability of partial unfolding fluctuations.From these results, we propose a model where a dynamic cross‐talk emerges between the chaperone dynamics states and remodelling of client‐interacting regions. This factor, coupled to the highly dynamic nature of the assemblies and the conformational heterogeneity of their interactions, provide the basis to regulating the functions of distinct assemblies during the chaperoning cycle.This article is protected by copyright. All rights reserved.

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The C-terminal region of the human p23 chaperone modulates its structure and function

Cited by 20 publications

References 46 publications

Identification of two p23 co‐chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities

Identification of two p23 co‐chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities

Hsp90 oligomerization process: How can p23 drive the chaperone machineries?

Molecular mechanisms of chaperone‐directed protein folding: Insights from atomistic simulations

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