APH1

APH1, short for anterior pharynx defective-1, is a name applied to a conserved family of multi-pass transmembrane proteins that function as regulatory subunits of the gamma-secretase protease complex. In vertebrates, three APH1 paralogs—APH1A, APH1B, and APH1C—participate in gamma-secretase assembly with the catalytic presenilin subunits (PSEN1/PSEN2), nicastrin, and PEN-2. APH-1 proteins are essential for complex maturation, stability, and activity, and they influence substrate selection and proteolysis of type I transmembrane substrates including the amyloid precursor protein (APP) and Notch receptors.

Structure and localization: APH-1 proteins are multi-pass membrane proteins localized to intracellular membranes and the sites of gamma-secretase activity, such as the endoplasmic reticulum, Golgi, and endosomal compartments. They form stable interactions with presenilin and other gamma-secretase components.

Genetic and functional highlights: Disruption or altered expression of APH1 paralogs reduces gamma-secretase activity, whereas differential expression can shift processing of substrates. In model systems, APH1 status modulates production of amyloid-beta peptides and Notch signaling outputs.

Clinical and research relevance: Because gamma-secretase activity governs production of amyloid-beta, APH1 variants and expression patterns are of interest in Alzheimer's disease research. Pharmacological strategies that modulate APH-1–containing gamma-secretase aim to decrease Aβ production while preserving Notch signaling, but achieving this selectively remains challenging. APH1 function has been studied in cell lines, mice, and other model organisms to understand the regulation of intramembrane proteolysis.

See also: gamma-secretase, presenilin, nicastrin, PEN-2, Notch signaling, amyloid precursor protein.