We propose to continue and to extend our studies of sequence/conformation relationships in polypeptides. In most of this work, we use synthetic peptides as models to pose questions about conformational behavior. In some studies, we seek to elucidate the conformational features responsible for biological activities. Several levels of conformational questions are included in the work proposed for the next project period, ranging from local features such as turns, to secondary structures, to domains, and on to protein folding. A new area that will be investigated is the recognition of incompletely folded chains by chaperones, a class of proteins that facilitate folding and assembly of proteins in vivo.
Specific aims of the next project period include studies of: 1) the contributions of hydrogen-bonding side chains to stability of various reverse turns; 2) the conformational influences of serine phosphorylation, with specific reference to the tau protein that occurs in paired helical filaments in Alzheimer's disease; 3) the bioactive conformation of gonadotropin releasing hormone; 4) inhibitors of farnesyl protein:transferase; 5) conformational specificity of Arg-Gly-Asp sequences in fibronectin and vitronectin receptor binding; 6) conformations adopted by domains of the LDL receptor; 7) the mechanism of folding of cellular retinoic acid binding protein; and 8) conformational features recognized by the E. coli chaperones GroEL and DnaK. The techniques we employ in all of the proposed work include circular dichroism, to assess tendencies to take up non-random conformational distributions and to monitor conformational changes, and nuclear magnetic resonance, to determine at a residue by residue level the conformational states preferred by the peptide under study. Our long-term goal is to shed light on the code relating amino acid sequence to conformational properties of polypeptides, and in this way to contribute to understanding of biological activities mediated by various sequences. The present proposal may directly contribute to several biomedical problems, including deposition of neurofibrillary tangles in Alzheimer's disease, oncogenesis by ras oncogenes, reproductive disorders, cell-cell contact inhibition, and hypercholesterolemia.
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