APH-1 (anterior pharynx-defective 1) is a proteingene product originally identified in the Notch signaling pathway in Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin.[1] APH-1 homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease.[2] All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin.[3] APH-1 contains a conserved alpha helix interaction motifglycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.[4]
References
↑Goutte C, Tsunozaki M, Hale VA, Priess JR. (2002). APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci USA 99(2):775-9. PMID11792846
↑Kaether C, Haass C, Steiner H. (2006). Assembly, trafficking and function of gamma-secretase. Neurodegener Dis 3(4-5):275-83. doi:10.1159/000095267PMID17047368
↑Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H. (2003). PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 278(10):7850-4. PMID12522139
↑Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, Pedersen K, Han W, Thomas P, Lundkvist J, Hao YH, Yu G. (2004). A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem 279(6):4144-52. doi:10.1074/jbc.M309745200PMID14627705
