The investigator proposes to continue and extend her studies of sequence/conformation relationships in polypeptides. She will explore projects that are unified by the central question of how amino acid sequence determines the three-dimensional structures of peptides and proteins. Specifically, the investigator will analyze the folding pathway of a predominantly beta-sheet protein, cellular retinoic acid binding protein (CRABP), using a multipronged approach; she will continue her efforts to understand the mode of action of molecular chaperones, with a focus on biophysical characterization of the roles and structures of these molecules -- included in this work will be continuing studies of the GroEL/ES/Mg-ATP system, structural and peptide- binding studies of members of the Hsp70 family of chaperones, and interactions of the GroEL system with CRABP; she will continue her collaborative examination of the structural requirements on the cytoplasmic tails of coated-pit receptors for internalization by endocytosis; she will initiate a collaboration to test design principles and conclusions derived from her studies of CRABP by expressing potential beta-turn and beta-sheet repeating segments in E. coli. All of this work will contribute in a fundamental way to an understanding of protein folding both in vitro and in vivo, and may also make significant contributions in the area of drug design. Furthermore, the results from these studies will aid in several health-related areas; elucidation of the structural principles and mode of substrate binding by a member of the beta-clamshell family that binds hydrophobic ligands, and specifically in this case a known morphogen, enhanced understanding of how protein folding occurs in the cell and what may go wrong, if it fails, elucidation of the mechanism by which cells internalize proteins, and improved bases for design of proteins with specific structural properties.
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