Chen et al. reveal the existence of large, multiprotease complexes that can process amyloid precursor protein (APP) and other substrates at the plasma membrane.
Like many transmembrane proteins, APP can be sequentially cleaved by different proteases in a process called regulated intramembrane proteolysis (RIP). APP’s extracellular domain is first removed by α-secretases such as ADAM10, or β-secretases like BACE1. γ-Secretase then cleaves APP within its transmembrane helix, releasing the protein’s intracellular domain and, if the protein was initially processed by β-secretase, the toxic Aβ peptide implicated in Alzheimer’s disease. The different proteases have been assumed to remain separate from each other in vivo, but Chen et al. discovered that γ- and α-secretases can associate with each other at the cell surface.
Members of the tetraspanin family of membrane proteins promoted the secretases’ interaction, which would likely allow substrates to be processed more efficiently. Indeed, the complexes were able to sequentially cleave APP-based substrates at their α and γ target sites.
Surprisingly, when cells were treated with γ-secretase inhibitors, α-secretase activity was enhanced (and β-secretase activity was reduced), indicating that cells possess feedback mechanisms to regulate the initial steps of RIP. In contrast, a compound that modulates γ-secretase’s cleavage site specificity had no effect on α- or β-secretase activity, suggesting that this class of drugs may have fewer side effects in Alzheimer’s patients.
Chen et al. also identified a separate interaction between β- and γ-secretase. The researchers now want to investigate whether other proteases involved in RIP form similar complexes.