Intramembrane aspartyl proteases glycine-x-glycine-aspartate (GxGD) active site motif. Signal Peptide Peptidases (SPPs) degrade signal peptides after protein secretion. SPP and SPP-like proteases participate in regulated intramembrane proteolysis (RIP), protein ectodomain shedding and cleavage of tailed anchored proteins Other members, Presenilin, cleaves β-amyloid precursor protein linked to Alzheimer’s disease. Presenilin homolog (PSH) from archaeon Methanoculleus marisnigri provided insight on structure and catalytic mechanism. Here, HM13 is linked to early-onset autosomal dominant Alzheimer disease.