Molecular mechanisms of tumor-cell markers: Structural insights into the STEAP and tetraspanin membrane protein families

Abstract

Cancer is the collective name for more than 200 diseases which are characterized by uncontrolled growth and division of a group of cells in the human body. If these cells form a mass with the potential to invade other parts of the body, this cell mass is defined as a malignant tumor. The molecular landscape of tumor-cell membranes is formed by proteins that stimulate the growth and survival of the tumor cell. These membrane proteins are classified as tumor markers and are important targets for cancer immunotherapy. In this PhD research, we investigated two membrane protein families, the ‘six-transmembrane epithelial antigen of the prostate’ proteins (STEAPs) and tetraspanins. Both STEAPs and tetraspanins are highly upregulated on the membranes of several tumors, but at the start of our research there were limited insights into the molecular mechanisms of these proteins. Thus, the goal of our research was to increase our understanding of the molecular mechanisms of STEAPs and tetraspanins, with the ultimate aim to allow for the design of new translational research strategies to target these membrane proteins in cancer. We solved the 3D structures of STEAPs and of the tetraspanin CD9 using cryo-electron microscopy. The function of STEAPs is to reduce iron and copper. The STEAP-structures allowed us to generate a model of how STEAPs transport electrons from inside the cell to extracellular metal ions. These molecular insights into the metalloreductase activity of STEAPs may be useful in the design of new therapeutic strategies to target STEAPs in cancer. Tetraspanins are known as ‘molecular organizers’ of the cell membrane because they cluster specific partner proteins in microdomains. Our structure of tetraspanin CD9 in complex with its partner protein EWI-F provide implications for the assembly of these microdomains.