Date of Award
Campus Access Thesis
Master of Science (MS)
Biotechnology and Biomedical Science
Kenneth L. Campbell
Kenneth C. Kleene
Studies of differential metabolism of the subunits of intact hCG by target tissues suggest protein hormones may contain information beyond that conveyed by the intact hormone. Such information may only be released if the intact proteins are modified so they can trigger non-classical transduction pathways or are released to act on secondary target cells. Modification likely involves digestion of the protein hormones to peptides as part of the process of clearing occupied protein-receptor complexes from target cell surfaces. To see if bioactive peptide products are formed, fragmentation of FSHα, FSHβ, LHβ, TSHβ, and hCGβ by known enzymes (trypsin, chymotrypsin, and cathepsins G, H, K, and D) was modeled in silico. New software, Protein Cyberase, was developed to predict protein fragmentations catalyzed by one or more enzymes in sequence; results show agreement with those of previously published programs. Proteolytic peptides of >5 v and <40 amino acids were matched as linear sequences or further characterized for three dimensional structures and then matched to similar structural motifs in known proteins by using proteomic tools: Smith-Waterman alignments, molecular dynamic modeling software (NAMD, VMD, and AMBER ff03 force field), and LabelHash. The matches found identify proteins that share the protein hormone-derived peptide motifs and that may be susceptible to modulation of their normal protein-protein interactions by the presence of the hormone-derived peptides. Linear alignments gave protein matches with identities with the hormone-derived peptides of >87% with no sequence gaps within the unrestricted PDB. Identified proteins include metabolic proteins responsible forintracellular metabolism and transduction. LabelHash identified three-dimensional structural motif matches (p < 0.0003) in the known structure-restricted PDB. These matches included hydrolases, oxidoreductases, and soluble hormones. The location of the matching domains at or near the surface of these proteins implies possible involvements of the domains in protein-protein interactions as per the initial hypothesis. The findings identify the best subjects for biochemical and cellular experiments to test the bioactivities of protein hormone peptides and suggest that these peptides may act either as secondary hormones or may act as direct intracellular modulators of cellular metabolism.
Vadher, Umaben S., "Proteolytic Fragments of Glycoprotein Hormones Show Homologies to Signal and Metabolic Proteins: Are the Peptide Fragments Biologically Active?" (2011). Graduate Masters Theses. 65.