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Frontiers of Oxidative Protein Folding and Assembly: Catalysis of Disulfide Formation Downstream of the Endoplasmic Reticulum

Final Report Summary - QSOX1BIOFUNC (Frontiers of Oxidative Protein Folding and Assembly: Catalysis of Disulfide Formation Downstream of the Endoplasmic Reticulum)

QSOX1 is an enzyme that catalyzes the introduction of disulfide cross-links into proteins in the Golgi apparatus and extracellularly. Most enzymes carrying out related functions act in the endoplasmic reticulum, so QSOX1 is unique. QSOX1 is also intriguing due to its over-production in many types of adenocarcinoma (cancer of secretory organs such as lung, pancreas, and breast). The aims of the project QSOX1BIOFUNC were to discover normal physiological roles of QSOX1 in mammals and to develop tools for inhibiting excess, tumor-induced QSOX1 as potential anti-metastatic cancer therapies. Though the manner in which QSOX1 affects cancer development was not known at the outset of the project, based on our preliminary work on QSOX1 activity in formation of the fibrous extracellular matrix produced by cells we hypothesized that the enzyme helps remodel the matrix microenvironment surrounding tumors. The desire to block this putative process inspired us to develop specific antibodies that inhibit QSOX1 activity. Treating mice with these antibodies after they had been injected with cells that cause the development of breast tumors slowed the growth of the tumors compared to control mice receiving generic antibodies. We also discovered that, in addition to the normal and pathological roles for QSOX1 in extracellular matrix formation, QSOX1 is involved in formation of the mucus coating that protects the digestive tract. Without QSOX1, mice readily develop colitis, an inflammation of the colon. The function of QSOX1 in mucus formation, however, appears to be carried out in the Golgi apparatus rather than extracellularly, such that it would be shielded from the effect of therapeutic QSOX1-inhibitory antibodies. In parallel with the studies of physiological effects of QSOX1, we shed light on its dynamic and complex enzymatic mechanism and used our knowledge to illuminate the electron-transfer mechanism used by the extensive family of “Protein Disulfide Isomerases,” which share sequence and structural similarity with a key catalytic region of QSOX1. Overall, the project produced fundamental insights into QSOX1 biochemistry and physiological functions, as well as practical tools that may be further developed to realize their therapeutic potential.