Determinants of organelle-specific activation of Proprotein Convertase 1

描述（由申请人提供）：蛋白转化酶（PCs），如PC1和furin，是一个普遍存在的进化上保守的丝氨酸蛋白酶超家族，负责介导多种加工步骤，以在细胞内产生活性蛋白和肽。由于过早的蛋白酶活性可能导致不适当的蛋白质激活、分选或降解，PC活性受到n端前肽的严格调节，这些前肽作为分子内伴侣（IMCs）的功能，最初折叠蛋白酶结构域，并作为催化抑制剂。尽管它们具有重叠的特异性，但IMC作为其同源催化结构域的抑制剂的能力指导了细胞器和ph特异性的激活

DESCRIPTION (provided by applicant): Proprotein convertases (PCs), such as PC1 and furin, are a ubiquitous super-family of evolutionarily conserved serine proteases responsible for mediating a diverse range of processing steps to generate active proteins and peptides within the cell. As premature protease activity can lead to inappropriate protein activation, sorting, or degradation, PC activity is stringently modulated by N-terminal propeptides that function as Intramolecular Chaperones (IMCs) to initially fold protease domains, and act as catalytic inhibitors. Although they share overlapping specificity, it is the ability of the IMC to act as an inhibitor of its cognate catalytic domain that directs the organelle- and pH-specific activation of PC1 and furin, allowing them to selectively cleave their substrates in compartment-specific manner in vivo. Mutations in IMCs of PC1 and furin underlie the aberrant activities seen in a range of endocrinopathies, including extreme obesity, abnormal glucose homeostasis, as well as cancer and heart disease. Despite devastating consequences on cellular homeostasis, the molecular and cellular determinants that modulate activation of PCs are poorly understood. Using an array of biochemical, biophysical, computational and molecular techniques, the goals of this proposal are to 1) determine how the IMC of PC1 acts as a pH sensor, and 2) develop specific inhibitors of PC1 activity.