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γ-secretase cleaves multiple substrates with essential roles from development to neurodegeneration, and its aberrant processing underlies human disorders including Alzheimer's disease (AD). Tian et al. now identify a domain in the β-amyloid precursor protein (APP) that inhibits γ-secretase activity and show that certain familial AD–linked APP mutations within this domain impair this inhibition, resulting in increased β-amyloid generation. The study thus reveals a novel mechanism whereby γ-secretase's activity is influenced by its own substrate.
An X-ray crystal structure of an organic anion transporter identifies it as an ion channel instead. Its similarity to an unrelated family of water channels raises evolutionary questions that have been recently bubbling up around membrane proteins.
