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Long-term Proposal Report Structural Study of Regulated Intramembrane Proteolysis

Regulated Intramembrane Proteolysis (RIP) is a highly conserved signaling mechanism, where a signaling molecule is cleaved within the lipid bilayer by an intramembrane protease. Traditional wisdom argued that proteolysis requires water; however, in RIP, both the protease and the substrate are integral membrane proteins and the cleavage occurs within the hydrophobic lipid bilayer. It has been most intriguing to scientists how water molecules and substrate get access to the active site of an intramembrane protease. Based on the function and predicted active site, the characterized intramembrane proteases are classified into 4 families: the metalloprotease site-2 protease (S2P), the serine protease Rhomboid, the aspartyl proteases Signal Peptide Peptidase (SPP) and Presenilin. Intramembrane proteases play important roles in a wide range of cellular functions. For example, S2P is a key player in sterol metabolism in cells; Rhomboid works in the Wnt signaling pathway; Presenilin is the most notorious intramembrane protease as it directly cleaves Amyloid Precursor Protein (APP) and results in the accumulation of β-amyloid peptide, the direct pathogen for Alzheimer’s disease. In order to understand the working mechanism of RIP, it requires highresolution structures of the intramembrane proteases both in the apo-form and in the substrate or inhibitor-bound forms. Successful determination of the proposed structures will also provide invaluable therapeutic potentials to fight deleterious diseases, such as Alzheimer’s disease and cardiovascular diseases. There were a number of important questions that we would like to address. In particular, we would like to understand what regulates the substrate access to the active site of the intramembrane proteases; what are the structure and function mechanism of SPP; and what are the structure and function mechanism of Presenilin? The proposed research aimed to address the above questions.