Molecular/Chemistry Chaperones and Hemoglobinopathies

University Of California San Francisco, San Francisco CA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): Protein folding abnormalities resulting from mutations in the coding regions of many genes represent the molecular basis for a large number of disease states. The solubility and stability of globin chains are altered by hundreds of mutations in the a- and b-globins. Therefore, diseases involving abnormal globin biogenesis are numerous (5% of the world's population are carriers of an inherited variant of hemoglobin). While the structure of the final folded state of each individual protein is largely determined by the primary amino acid sequence specified by the nucleotide sequence of the gene encoding it, it has become clear that a class of protein molecules known as molecular chaperones can modulate the rate of proper protein folding events and determine the degree to which polypeptides enter into non-productive pathways of folding. Furthermore, the rate of turnover of the wild-type (wt) and mutant forms of protein species by the cellular proteolytic machinery can be influenced by the action of various molecular chaperones. Finally, small nonprotein molecules acting as chemical chaperones can affect changes in the disposition of mutant gene products as they partition between non-native and native states. The action of the chemical chaperones on the polypeptide substrate or upon the protein folding environment often results in changes in the maturation rate, half-life and function of the mutant protein to where they approach that of the wild type species. We propose to examine folding pathway and assembly of globin chains during and after translation of the wild type and a number of mutant globin polypeptides. Special focus will be placed on study of the interactions with and actions of molecular chaperones with regard to final folded structure, solubility, stability and function of the globin chain variants. We will determine whether abnormally folded globin chains have any impact upon the levels and activities of the various molecular chaperones. Finally, through systematically changing the protein folding environment via small chemical chaperones, we will attempt to alter the fate of mutant globin chains. While the proposed research is of a basic biochemical nature, we believe it should facilitate the translation to approaches likely to have an immediate clinical impact.