An extensive study of the structure of parathyroid hormone (PTH) and the relationship of its structure to its interaction with kidney cell receptors is proposed. This work requires: the preparation of many specific fragments and derivatives of PTH, the preparation of a high affinity, biologically active tracer of the hormone, special methods for probing hormone structure (such as NMR spectroscopy), assays of specific interactions of receptors with the hormone, preparations of kidney cells responsive to the hormone, generation of antibodies against specific regions of the hormone, and methods for fractionation of kidney cells to isolate specific organelles, for its successful completion. The development and use of these methods and tools are described. The goals are to examine the conformation of PTH in solution, to identify the structural features of PTH which are essential for its binding to kidney receptors, to study the nature of the hormone's interaction with its receptors, to probe cellular responses to various chemically modified forms and fragments of PTH, and to determine the structural feature of the hormone important in generating a cellular response and for cellular uptake. We will also search for structural and functional aspects of the hormone which may be helpful in defining the role of the C-terminal 50 amino acids which, at the present, have not been found to have any particular function. This work is unique in that it focuses on design of experiments and interpretation of results based on a specific model for the solution conformation of PTH. Further the proposed studies all involve the 84 amino acid native hormone molecule, rather than the small 34 amino acid fragment used by others in related studies. The work will result in better understanding of the molecular and cellular aspects of the actions of this hormone which is essential for normal calcium and phosphate metabolism in man. It may also result in new PTH-derived peptides which have properties useful in treatment of hyperparathyrodism and hypoparathyroidism, kidney disease and metabolic bone disease. Such information will enhance our ability to deal clinically with such metabolic diseases as primary hyperparathyroidism, secondary hyperparathyroidism of renal origin, and parathyroid hormone related bone disease.
| Laethem, R; Zull, J E (1990) Characterization of the interaction of parathyroid hormone with the mitochondrial ATPase. Arch Biochem Biophys 282:161-9 |
| Laethem, R; Zull, J E (1988) The beta-subunit of the bovine mitochondrial F1 ATPase specifically binds the amino terminal domain of parathyroid hormone. Mol Cell Endocrinol 59:155-9 |
