Osmolytes as Modulators of Conformational Changes in Serpins
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Michelle K.M. Chow
Abstract
Protein misfolding and aggregation play an integral role in many diseases. The misfolding of the serpin (SERine Proteinase INhibitor) α1-antitrypsin results in the accumulation of insoluble polymers within hepatocytes and α1-antitrypsin deficiency in plasma, predisposing patients to liver cirrhosis and emphysema. We have examined the effect of three naturally occurring osmolytes, sarcosine, glycine betaine and trimethylamine Noxide, on conformational changes in α1-antitrypsin. All three solutes protected native α1-antitrypsin against thermally induced polymerisation and inactivation in a concentrationdependent manner. Further spectroscopic analysis showed that sarcosine stabilises the native conformation of α1-antitrypsin, thus hindering its conversion to an intermediate state and subsequent polymerisation. On refolding in the presence of sarcosine, α1-antitrypsin formed a heterogeneous population, with increasing proportions of molecules adopting an inactive conformation in higher concentrations of the osmolyte. These data show that sarcosine can be used to prevent abnormal structural changes in native α1-antitrypsin, but is ineffective in facilitating the correct folding of the protein. The implications of these results in the context of conformational changes and states adopted by α1-antitrypsin are discussed.
Copyright © 2001 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- An Overview of Endosymbiotic Models for the Origins of Eukaryotes, Their ATP-Producing Organelles (Mitochondria and Hydrogenosomes), and Their Heterotrophic Lifestyle
- A Microsomal Ecdysone-Binding Cytochrome P450 from the Insect Locusta migratoria Purified by Sequential Use of Type-II and Type-I Ligands
- The Large Cytoplasmic Loop of the Glucose Transporter GLUT1 Is an Essential Structural Element for Function
- Visual Representation by Atomic Force Microscopy (AFM) of Tomato Spotted Wilt Virus Ribonucleoproteins
- Elimination of Hydrocortisone from the Medium Enables Tissue Plasminogen Activator Gene Expression by Normal and Immortalized Nonmalignant Human Epithelial Cells
- Molecular Cloning and Biochemical Characterisation of Proteases from Staphylococcus epidermidis
- Splice Variants of Human Cathepsin L mRNA Show Different Expression Rates
- Osmolytes as Modulators of Conformational Changes in Serpins
- Protective Activity of Aromatic Amines and Imines against Oxidative Nerve Cell Death
- Nitric Oxide Generation in Aqueous Solutions of Cigarette Smoke and Approaches to Its Origin
- A Recombinant scFv/Streptavidin-Binding Peptide Fusion Protein for the Quantitative Determination of the Scorpion Venom Neurotoxin AahI
