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paper8 - Advance Online...

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Lateral gate Membrane Presumed substrate access Catalysis C N Substrate Cap WR x G G 1 2 3 4 5 6 N u c l e o p h i l i c a t t a c k S H Proteases are some of the most potent tools to which a cell has access, because, unlike most other protein-modifying enzymes, they cata- lyse an essentially irreversible reaction — the breaking of peptide bonds. This can obviously be used to degrade unwanted proteins, but proteases also have many vital regulatory func- tions 1 . In the past few years, a class of proteases called intramembrane proteases has been dis- covered. These comprise diverse families, but all have multiple transmembrane domains and an active site apparently embedded within the hydrophobic region of cell membranes. All intramembrane proteases share the curious property of cutting their membrane- spanning protein targets in the transmem- brane regions — that is, they are thought to perform the peptide-cleaving reaction (which requires water) within the lipid bilayer of cel- lular membranes 2 . As this is an environment where water is traditionally assumed to be in short supply, this is a somewhat heretical idea. This has contributed to intramembrane pro- teases being only slowly accepted into the fold of classical proteases, despite their essential roles in various biological and medically rel- evant processes. In a landmark paper published on Nature ’s website today, Wang et al . 3 present the first high-resolution structure of an intram- embrane protease. At last the doubters can be satisfied, and we can begin to understand these enigmatic enzymes in atomic detail. The rhomboid family were proposed to be serine-type intramembrane proteases 4 . Their name, and the first to be identified, comes from Drosophila Rhomboid-1. This enzyme cuts the membrane-tethered precursor of epidermal growth factor within the membrane, thereby releasing the extracellular domain 4 , which then signals to surrounding cells, triggering a vari- ety of developmental decisions. Rhomboids are found in almost all organisms 5,6 and, although little is known about their function in most species, they have been implicated in biological processes as diverse as mitochondrial function, invasion of host cells by apicomplexan parasites (including Plasmodium and
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