The pH-Dependent Specificity of Cathepsin S and Its Implications for Inflammatory Communications and Disease.

Abstract

Proteases have two major roles in health and disease: making functional changes to proteins as a post-translational modification and degradation of proteins as a regulatory or waste management mechanism. The cysteine protease cathepsin S serves both of these functions. It digests antigens in the adaptive immune system and is associated with many autoimmune diseases and cancers. Here, we show that the catalytic specificity of human cathepsin S is regulated by the pH conditions of its environment and identify the structural determinants of this switch. Peptide digests show that the proteolytic specificity of cathepsin S narrows at extracellular pH. Crystal structures reveal that a lysine residue descends into the S3 pocket of the active site above pH 7, which can be explained by changes in the protein's surface charge at that pH. We discuss biological compartment transitions and disease processes associated with cathepsin S in which these pH-dependent specificity switches may be triggered.