"Death, taxes, and rhomboids: Understanding the ubiquitous roles of the rhomboid protein super-family".

Abstract

The rhomboid super-family 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 has made specific functional characterisation difficult. Where function is known, members appear to be not imminently necessary for life, but organisational or housekeeping in nature. Historically, active protease members have been the focus of research, due to the ease of biochemical characterisation through monitoring proteolytic cleavage. The active members appear to possess conserved and specific recognition motifs for substrates, although no consensus sequence for substrates exist. Instead substrate access and recognition appear to occur through recognition by dynamics. In recent years, bioinformatic work has shifted focus towards catalytically inactive members, and the functional characterisation of these numerous but oft 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.