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The Rhomboid Superfamily: Structural Mechanisms and Chemical Biology Opportunities
Anežka Tichá1, Blanka Collis2, Kvido Strisovsky2
1Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague, 166 10, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 32, Prague, 121 08, Czech Republic.
Abstract:
The rhomboid superfamily of transmembrane (TM) proteins includes intramembrane serine proteases and several classes of pseudoprotease. Rhomboid-like proteins occur widely across evolution and comprise biologically important regulators of fate of membrane proteins, influencing their proteolysis, trafficking, or degradation. In this review, we discuss how structural and mechanistic insights into the action of rhomboid proteases can inform on the mechanism of the pseudoproteases, and discuss the impact of structural understanding on the development of inhibitors and other chemical biology tools for these proteins. Development of modulators would be particularly relevant for the iRhoms, which are key regulators of ADAM17 and, hence, tumor necrosis factor (TNF) and epidermal growth factor receptor (EGFR) signaling, two medically important pathways.
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