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The preparation and characterization of IGF2 prohormones
Potalitsyn, Pavlo ; Žáková, Lenka (advisor) ; Obšilová, Veronika (referee) ; Hudeček, Jiří (referee)
Insulin-like growth factors 1 and 2 are protein hormones that share similar structural and functional features with insulin. They are commonly abbreviated as IGF1 and IGF2. They play important roles in prenatal development and throughout lifespan. Stimulation of growth of all cell types and significant metabolic effects also belong among their known functions. Dysregulation of their activity or elevated levels were observed in a number of diseases such as diabetes mellitus type 2, cancer, hyperthyroidism, amyotrophic lateral sclerosis, muscle dystrophy, acromegaly, Laron dwarfism and other disorders. Functions of IGF2 are less studied than functions of the other members of the family and even less is known about precursors of IGF2. To address these issues we started with production of IGF2 analogues with enhanced specificity to IR for better understanding the mechanism of receptor activation by IGF2. We produced site-specific analogues modified at sites important for receptor binding. IGF2 analogue with Phe48His mutation is the strongest IGF2-derived binder for IR-A reported ever and it is able to activate IR-A to about 60% of insulin ability. We developed new rapid, robust, and sensitive binding assays for testing of ligands of the receptor for IGF2 (IGF2R). First, we immobilized domain 11 of...
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