Death, taxes, and rhomboids: Understanding the ubiquitous roles of the rhomboid protein superfamily

The rhomboid superfamily is the largest family of membrane proteins, containing over 122,000 members (both active and inactive proteases) across nearly all domains of life. The high number of members, as well as the conserved roles undertaken by members, indicates an ancient origin and nature of function. However, the high structural similarity and multiple active homologs per species or cell have made specific functional characterization difficult. Where function is known, members appear to be not imminently necessary for life but organizational or housekeeping in nature. Historically, active protease members have been the focus of research because of the ease of biochemical characterization through monitoring proteolytic cleavage. The active members appear to possess conserved and specific recognition motifs for substrates, although no consensus sequence for substrates exists. Instead, substrate access and recognition appear to occur through recognition by dynamics. In recent years, bioinformatic work has shifted focus toward catalytically inactive members and the functional characterization of these numerous but often forgotten "dead" proteases. These inactive proteases are now known to play key roles in the recognition and retrotranslocation of poor-quality membrane proteins. Recent work on the rhomboid-fold's unique ability to thin the lipid bilayer has enhanced mechanistic knowledge of both inactive and active protease function. Due to the ubiquitous presence of rhomboid members and their implications in a wide range of disease states, they are high-priority pharmaceutical targets; however, development of specific inhibitors has been hampered by the tight conservation of both the active site and the common rhomboid fold.