Membrane protein secretases

A diverse range of membrane proteins of Type 1 or Type II topology also occur as a circulating, soluble form. These soluble forms are often derived from the membrane form by proteolysis by a group of enzymes referred to collectively as 'secretases' or 'sheddases'. The cleavage generally occurs close to the extracellular face of the membrane, releasing physiologically active protein. This secretion process also provides a mechanism for down-regulating the protein at the cell surface. Examples of such post-translational proteolysis are seen in the Alzheimer's amyloid precursor protein, the vasoregulatory enzyme angiotensin converting enzyme, transforming growth factor-alpha, the tumour necrosis factor ligand and receptor superfamilies, certain cytokine receptors, and others. Since the proteins concerned are involved in pathophysiological processes such as neurodegeneration, apoptosis, oncogenesis and inflammation, the secretases could provide novel therapeutic targets. Recent characterization of these individual secretases has revealed common features, particularly sensitivity to certain metalloprotease inhibitors and upregulation of activity by phorbol esters. It is therefore likely that a closely related family of metallosecretases controls the surface expression of multiple integral membrane proteins. Current knowledge of the various secretases are compared in this Review, and strategies for cell-free assays of such proteases are outlined as a prelude to their ultimate purification and cloning.