Isolation and Imaging of the Zymogen ADAM17 Protein Structure Using Electron Microscopy

Abstract

By Maria Rich, Medical Sciences

Advisor: Tom Seegar

Award: Excellence in Research Communication

Presentation ID: 48

Abstract: ADAMs (A disintegrin and metalloproteinase) are a family of transmembrane proteins functioning in cell adhesion, intercellular communication, and signal transduction. There are 21 ADAMs encoded in the human genome, 13 of which are known or predicted to be catalytically active enzymes that play key roles in the shedding of membrane-tethered proteins, changing their biological functions. ADAM17, a catalytically active family member, is a critical regulator of mammalian development and has been shown to play a vital role in human pathogenesis. ADAM17 is initially translated in the cell as a zymogen (a precursor to an enzyme) bound by a prodomain that functions to control enzyme latency, thereby disabling the enzyme from processing protein substrates at disproportionate times and subcellular compartments. While some of the ADAM17's domains have been structurally categorized, a zymogen form of the enzyme remains undetermined and clear mechanistic details into enzyme activation are missing. To address this gap, we have purified the ADAM17 into a detergent micelle and developed preliminary structural information to categorize the atomic details of the ADAM17 zymogen. Bridging the gap between ADAM17 function and structure may assist in furthering our understanding of neurodegenerative pathology, chronic inflammatory conditions, cancers, and immune responses.