APH-1 (anterior pharynx-defective 1) is a protein gene product originally identified in the Notch signaling pathway in ''Caenorhabditis elegans'' as a regulator of the cell-surface localization of nicastrin.〔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. PMID 11792846〕 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.〔Kaether C, Haass C, Steiner H. (2006). Assembly, trafficking and function of gamma-secretase. ''Neurodegener Dis'' 3(4-5):275-83. PMID 17047368〕 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.〔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. PMID 12522139〕 APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.〔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. PMID 14627705〕
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