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Michelle K.M. Chow, Glyn L. Devlin, Stephen P. Bottomley
Osmolytes as Modulators of Conformational Changes in Serpins
Protein misfolding and aggregation play an integral role in many diseases. The misfolding of the serpin (SERine Proteinase INhibitor) ?1-antitrypsin results in the accumulation of insoluble polymers within hepatocytes and ?1-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 ?1-antitrypsin. All three solutes protected native ?1-antitrypsin against thermally induced polymerisation and inactivation in a concentrationdependent manner. Further spectroscopic analysis showed that sarcosine stabilises the native conformation of ?1-antitrypsin, thus hindering its conversion to an intermediate state and subsequent polymerisation. On refolding in the presence of sarcosine, ?1-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 ?1-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 ?1-antitrypsin are discussed.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 382, 11/2001
Pages: 1593 - 1599