The roles of molecular chaperones in regulating cell metabolism

Binder, M.; Pedley, Anthony M.

doi:10.1002/1873-3468.14682

Cited by 11 publications

(3 citation statements)

References 223 publications

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“…The participation of Hsp90 and Hsp70 chaperone families on human metabolic enzymes espetially their participation in enzymatic activities as participating in translocation and degradation of methabolic enzymes highlights their participation in disease-related disorders [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Ab initio protein structure prediction: the necessary presence of external force field as it is delivered by Hsp40 chaperone

Roterman,

Stapor,

Konieczny

2023

BMC Bioinformatics

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Background The aqueous environment directs the protein folding process towards the generation of micelle-type structures, which results in the exposure of hydrophilic residues on the surface (polarity) and the concentration of hydrophobic residues in the center (hydrophobic core). Obtaining a structure without a hydrophobic core requires a different type of external force field than those generated by a water. The examples are membrane proteins, where the distribution of hydrophobicity is opposite to that of water-soluble proteins. Apart from these two extreme examples, the process of protein folding can be directed by chaperones, resulting in a structure devoid of a hydrophobic core. Results The current work presents such example: DnaJ Hsp40 in complex with alkaline phosphatase PhoA-U (PDB ID—6PSI)—the client molecule. The availability of WT form of the folding protein—alkaline phosphatase (PDB ID—1EW8) enables a comparative analysis of the structures: at the stage of interaction with the chaperone and the final, folded structure of this biologically active protein. The fuzzy oil drop model in its modified FOD-M version was used in this analysis, taking into account the influence of an external force field, in this case coming from a chaperone. Conclusions The FOD-M model identifies the external force field introduced by chaperon influencing the folding proces. The identified specific external force field can be applied in Ab Initio protein structure prediction as the environmental conditioning the folding proces.

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Section: Discussionmentioning

confidence: 99%

Ab initio protein structure prediction: the necessary presence of external force field as it is delivered by Hsp40 chaperone

Roterman,

Stapor,

Konieczny

2023

BMC Bioinformatics

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“…Methenyltetrahydrofolate synthetase (MTHFS, EC 6.3.3.2), an enzyme catalyzing the ATP-dependent formation of cofactor 5,10-methenyltetrahydrofolate used by TrifGART and ATIC was shown to colocalize with two tested enzymes of the purinosome, TrifGART and FGAMS ( Field et al, 2011 ). Chaperones and co-chaperones from the Hsp70/Hsp90 system were also validated to regulate the formation of the purinosome ( Figure 7 ) by directly interacting with PPAT and FGAMS ( Binder and Pedley, 2013 ; French et al, 2013 ; Pedley et al, 2018 ).…”

Section: Navigating the Complexities Of Metabolon Formation For Finer...mentioning

confidence: 98%

A journey into the regulatory secrets of the de novo purine nucleotide biosynthesis

Ayoub,

Gedeon,

Munier-Lehmann

2024

Front. Pharmacol.

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De novo purine nucleotide biosynthesis (DNPNB) consists of sequential reactions that are majorly conserved in living organisms. Several regulation events take place to maintain physiological concentrations of adenylate and guanylate nucleotides in cells and to fine-tune the production of purine nucleotides in response to changing cellular demands. Recent years have seen a renewed interest in the DNPNB enzymes, with some being highlighted as promising targets for therapeutic molecules. Herein, a review of two newly revealed modes of regulation of the DNPNB pathway has been carried out: i) the unprecedent allosteric regulation of one of the limiting enzymes of the pathway named inosine 5′-monophosphate dehydrogenase (IMPDH), and ii) the supramolecular assembly of DNPNB enzymes. Moreover, recent advances that revealed the therapeutic potential of DNPNB enzymes in bacteria could open the road for the pharmacological development of novel antibiotics.

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“…The main players of the chaperone system are the heat shock proteins (HSPs) and the master transcription factor, heat shock factor 1 (HSF1). Chaperone proteins such as HSPs are controlled by HSF1 and undertake a wide range of cellular functions including protein homeostasis, cell survival and cell metabolism (Binder & Pedley, 2023;Kim et al, 2013;Margulis et al, 2020). In unstressed condition, some HSPs are present in steady level to facilitate the daily cellular function and maintain homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel small molecule chaperone activators for neurodegenerative disease treatment

Ho,

Jeganathan,

Bictash

et al. 2024

Preprint

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A pathological hallmark of neurodegenerative disease is the accumulation of aberrant protein aggregates which contribute to the cytotoxicity and are therefore a target for new therapy development. One key machinery to manage cellular protein homeostasis is the chaperones proteins, the heat shock proteins (HSPs) which are known to target aberrant proteins including TDP-43, tau and amyloid and rescue neurodegeneration in various disease models. As an attempt to target HSP activation for neurodegeneration therapy, we develop a drug screening assay to search compounds that activate the master regulator of HSPs, the transcription factor heat shock factor 1 (HSF1). As HSF1 is bound by HSP90 which prevents its activation, we develop a NanoBRET assay, which allows us to monitor and quantify the HSF1-HSP90 interaction in living cells to screen for compounds disrupting this interaction and thereby releasing HSF1 for activation. After the assay was optimised and validated for its robustness and reliability, a two thousand compound library was screened which produced 10 hits including a couple of known HSP90 inhibitors. Follow-up functional study showed that one of the hit oxyphenbutazone (OPB) significantly reduces the accumulation of insoluble TDP-43 in a cell model, displaying no signs of stress or toxicity. Further works are needed to characterise the mode-of-action of OPB in HSF1 activation and aberrant protein reduction, and the physiological impact of OPB on TDP-43 needs to be examined in an in vivo model. However, this study demonstrates a viable strategy for new drug discovery in targeting aberrant proteins and identifies potential candidates for translation into neurodegenerative disease treatment.

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The roles of molecular chaperones in regulating cell metabolism

Cited by 11 publications

References 223 publications

Ab initio protein structure prediction: the necessary presence of external force field as it is delivered by Hsp40 chaperone

Ab initio protein structure prediction: the necessary presence of external force field as it is delivered by Hsp40 chaperone

A journey into the regulatory secrets of the de novo purine nucleotide biosynthesis

Identification of novel small molecule chaperone activators for neurodegenerative disease treatment

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