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Effects of ligand binding on the stability of aldo-keto reductases: Implications for stabilizer or destabilizer chaperones.

ABSTRACT: Ligands such as enzyme inhibitors stabilize the native conformation of a protein upon binding to the native state, but some compounds destabilize the native conformation upon binding to the non-native state. The former ligands are termed "stabilizer chaperones" and the latter ones "destabilizer chaperones." Because the stabilization effects are essential for the medical chaperone (MC) hypothesis, here we have formulated a thermodynamic system consisting of a ligand and a protein in its native- and non-native state. Using the differential scanning fluorimetry and the circular dichroism varying the urea concentration and temperature, we found that when the coenzyme NADP+ was absent, inhibitors such as isolithocholic acid stabilized the aldo-keto reductase AKR1A1 upon binding, which showed actually the three-state folding, but destabilized AKR1B10. In contrast, in the presence of NADP+ , they destabilized AKR1A1 and stabilized AKR1B10. To explain these phenomena, we decomposed the free energy of stabilization (??G) into its enthalpy (??H) and entropy (??S) components. Then we found that in a relatively unstable protein showing the three-state folding, native conformation was stabilized by the negative ??H in association with the negative ??S, suggesting that the stabilizer chaperon decreases the conformational fluctuation of the target protein or increase its hydration. However, in other cases, ??G was essentially determined by the delicate balance between ??H and ??S. The proposed thermodynamic formalism is applicable to the system including multiple ligands with allosteric interactions. These findings would promote the development of screening strategies for MCs to regulate the target conformations.

SUBMITTER: Kabir A

PROVIDER: S-EPMC5119574 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Effects of ligand binding on the stability of aldo-keto reductases: Implications for stabilizer or destabilizer chaperones.

Kabir Aurangazeb A Honda Ryo P RP Kamatari Yuji O YO Endo Satoshi S Fukuoka Mayuko M Kuwata Kazuo K

Protein science : a publication of the Protein Society 20160919 12

Ligands such as enzyme inhibitors stabilize the native conformation of a protein upon binding to the native state, but some compounds destabilize the native conformation upon binding to the non-native state. The former ligands are termed "stabilizer chaperones" and the latter ones "destabilizer chaperones." Because the stabilization effects are essential for the medical chaperone (MC) hypothesis, here we have formulated a thermodynamic system consisting of a ligand and a protein in its native- a ...[more]

PMID: 27595938

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Project description:The aldo-keto reductase (AKR) protein superfamily contains >190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation by-products. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5?-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the ?-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37kDa monomers, have an (?/?)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP(+) is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short-chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist world-wide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionarily conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease.

Dataset Information

Effects of ligand binding on the stability of aldo-keto reductases: Implications for stabilizer or destabilizer chaperones.

Publications

Effects of ligand binding on the stability of aldo-keto reductases: Implications for stabilizer or destabilizer chaperones.

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