The prohormone convertases PC1/3 and PC2, encoded by the genes PCSK1 and PCSK2 respectively, are the endoproteolytic enzymes responsible for the liberation of opioid active peptides from larger precursor proteins. Past work supported by this grant has described the maturation pathways of these enzymes in neural and endocrine cells; detailed their biochemical properties; developed specific convertase inhibitors; and elaborated their respective roles in opioid peptide production. Recently, in collaboration with clinicians who have identified children with novel rare mutations in PCSK1, we have studied the biochemical properties of mutant human and mouse PC1/3 proteins, and have shown that a mutant mouse PC1/3 protein is subject targeting defects which are likely to result in secretory system stress. In the current proposal, we would like to build upon these results by testing the idea that both common and rare PC1/3 mutations cause their profound physiological effects on human health by influencing the secretory biology of neurons and endocrine cells. We propose specific cell biology experiments to test the hypothesis that endoplasmic reticulum stress contributes to the functional impairment produced by PCSK1 mutant proteins. Based in our previous finding that mouse PC1/3 proteins oligomerize, we further propose that dominant negative interactions play a major role in human PC1/3 heterozygote phenotypes, potentially affecting proopiomelanocortin processing to certain bioactive peptides involved in satiety signaling. The ability of mutant PC1/3s to bind proSAAS, the endogenous PC1/3 binding protein, will also is examined, with the idea that mutants may exhibit aberrant binding. In the second aim, we propose to generate new mouse models for PCSK1-associated human obesity in order to provide in vivo corroboration of effects found in cell culture; and to further define te physiology underlying the strong obesity risk known to be associated with PCSK1 polymorphisms and mutations. These two aims, focusing on the cell biology and physiology of human PC1/3 mutants, build upon our substantial cell progress during the last cycle on human prohormone convertases. The results of these studies will illuminate the cell biological and biochemical mechanisms controlling neuropeptide and peptide hormone production that contribute to human susceptibility to disease.
This proposal addresses the production of peptide signaling hormones by studying human mutants of the enzymes which cut these peptides out of larger proteins. Because people with these particular mutations are obese, we will learn about peptide-mediated obesity mechanisms through these studies.
| Hardes, Kornelia; Ivanova, Teodora; Thaa, Bastian et al. (2017) Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin. ChemMedChem 12:613-620 |
| Ivanova, Teodora; Hardes, Kornelia; Kallis, Stephanie et al. (2017) Optimization of Substrate-Analogue Furin Inhibitors. ChemMedChem 12:1953-1968 |
| Winters, Alexandra; Ramos-Molina, Bruno; Jarvela, Timothy S et al. (2017) Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population. Diabetes Res Clin Pract 131:82-90 |
| Ramos-Molina, B; Martin, M G; Lindberg, I (2016) PCSK1 Variants and Human Obesity. Prog Mol Biol Transl Sci 140:47-74 |
| Ramos-Molina, Bruno; Lindberg, Iris (2015) Phosphorylation and Alternative Splicing of 7B2 Reduce Prohormone Convertase 2 Activation. Mol Endocrinol 29:756-64 |
| Hardes, Kornelia; Becker, Gero L; Lu, Yinghui et al. (2015) Novel Furin Inhibitors with Potent Anti-infectious Activity. ChemMedChem 10:1218-31 |
| Lindberg, Iris; Shorter, James; Wiseman, R Luke et al. (2015) Chaperones in Neurodegeneration. J Neurosci 35:13853-9 |
| Ramos-Molina, Bruno; Lick, Adam N; Nasrolahi Shirazi, Amir et al. (2015) Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors. PLoS One 10:e0130417 |
| Blanco, Elias H; Ramos-Molina, Bruno; Lindberg, Iris (2015) Revisiting PC1/3 Mutants: Dominant-Negative Effect of Endoplasmic Reticulum-Retained Mutants. Endocrinology 156:3625-37 |
| Ramos-Molina, Bruno; Lick, Adam N; Blanco, Elias H et al. (2015) Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays. Biochem Pharmacol 96:107-18 |
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