Structural and Functional Analysis of Two Parvalbumins of Extramuscular Origin

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The parvalbumins were originally identified as calcium-binding cytoplasmic proteins in striated muscle where they are thought to function as calcium buffers. The subject of this research is the structure and function of two members of the parvalbumin family of proteins from non-muscle tissues. The parvalbumin, oncomodulin, binds calcium and magnesium far less tightly than rat parvalbumin, despite 53% sequence identity. Production and characterization of additional site-specific variants of oncomodulin will further elucidate the factors responsible for ion-binding affinity in this family of calcium binding proteins. These results should have relevance not only to calcium-binding proteins, but to protein- ligand interactions in general. A surprising result of prior studies was the finding that a molecule previously known as Avian Thymic Hormone (ATH) is a member of the parvalbumin family, expressed specifically in the thymus. Avian thymic hormone is believed to facilitate avian T-lymphocyte maturation, but virtually nothing is known about its mechanism of action. Pursuit of this finding by identifying a receptor for ATH on bone marrow precursor cells and/or immature lymphocytes is a second major goal of this proposal. Characterization of the receptor should provide insight into the physiological significance of the parvalbumin-like thymic hormones. Avian thymic hormone and the muscle-associated parvalbumin from chicken are both expressed in a tissue-specific manner. Comparison of regulatory sequences in the two parvalbumin genes and characterization of specific DNA-binding proteins should provide insight into regulation of tissue-specific gene expression. Parvalbumins are calcium-binding proteins believed to function as cytoplasmic calcium ion buffers in muscle. There is evidence to suggest that they play additional, possibly regulatory, roles in non-muscle tissues. This research is directed toward understanding the molecular structure and cellular function of these proteins. The results of this research will contribute new knowledge concerning the molecular basis for the role of calcium binding proteins in cellular signaling.