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Protein refolding by pH-triggered chaperone binding and release.

ABSTRACT: Molecular chaperones are typically either adenosine triphosphate (ATP) dependent or rely heavily on their ATP-dependent chaperone counterparts in order to promote protein folding. This presents a challenge to chaperones that are localized to ATP-deficient cellular compartments. Here we describe a mechanism by which the pH-regulated acid stress chaperone HdeA is capable of independently facilitating the refolding of acid-denatured proteins in the bacterial periplasm, which lacks both ATP and ATP-dependent chaperone machines. Our results are consistent with a model in which HdeA stably binds substrates at low pH, thereby preventing their irreversible aggregation. pH neutralization subsequently triggers the slow release of substrate proteins from HdeA, keeping the concentration of aggregation-sensitive intermediates below the threshold where they begin to aggregate. This provides a straightforward and ATP-independent mechanism that allows HdeA to facilitate protein refolding. Unlike previously characterized chaperones, HdeA appears to facilitate protein folding by using a single substrate binding-release cycle. This cycle is entirely regulated by the external environment and is therefore energy-neutral for the bacteria.

SUBMITTER: Tapley TL

PROVIDER: S-EPMC2803140 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Protein refolding by pH-triggered chaperone binding and release.

Tapley Timothy L TL Franzmann Titus M TM Chakraborty Sumita S Jakob Ursula U Bardwell James C A JC

Proceedings of the National Academy of Sciences of the United States of America 20091231 3

Molecular chaperones are typically either adenosine triphosphate (ATP) dependent or rely heavily on their ATP-dependent chaperone counterparts in order to promote protein folding. This presents a challenge to chaperones that are localized to ATP-deficient cellular compartments. Here we describe a mechanism by which the pH-regulated acid stress chaperone HdeA is capable of independently facilitating the refolding of acid-denatured proteins in the bacterial periplasm, which lacks both ATP and ATP- ...[more]

PMID: 20080625

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Project description:AlphaA-crystallin is a molecular chaperone; it prevents aggregation of denaturing proteins. We have previously demonstrated that upon modification by a metabolic alpha-dicarbonyl compound, methylglyoxal (MGO), alphaA-crystallin becomes a better chaperone. AlphaA-crystallin also assists in refolding of denatured proteins. Here, we have investigated the effect of mild modification of alphaA-crystallin by MGO (with 20-500 microM) on the chaperone function and its ability to refold denatured proteins. Under the conditions used, mildly modified protein contained mostly hydroimidazolone modifications. The modified protein exhibited an increase in chaperone function against thermal aggregation of beta(L)- and gamma-crystallins, citrate synthase (CS), malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) and chemical aggregation of insulin. The ability of the protein to assist in refolding of chemically denatured beta(L)- and gamma-crystallins, MDH and LDH, and to prevent thermal inactivation of CS were unchanged after mild modification by MGO. Prior binding of catalytically inactive, thermally denatured MDH or the hydrophobic probe, 2-p-toluidonaphthalene-6-sulfonate (TNS) abolished the ability of alphaA-crystallin to assist in the refolding of denatured MDH. However, MGO modification of chaperone-null TNS-bound alphaA-crystallin resulted in partial regain of the chaperone function. Taken together, these results demonstrate that: 1) hydroimidazolone modifications are sufficient to enhance the chaperone function of alphaA-crystallin but such modifications do not change its ability to assist in refolding of denatured proteins, 2) the sites on the alphaA-crystallin responsible for the chaperone function and refolding are the same in the native alphaA-crystallin and 3) additional hydrophobic sites exposed upon MGO modification, which are responsible for the enhanced chaperone function, do not enhance alphaA-crystallin's ability to refold denatured proteins.

Dataset Information

Protein refolding by pH-triggered chaperone binding and release.

Publications

Protein refolding by pH-triggered chaperone binding and release.

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