Gamma secretase

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 39-42 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of the Notch protein.

ubunits and assembly

The gamma secretase complex has not yet been fully characterizedChen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P. (2006). TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. "Nature" 440:1208-1212. PMID 16641999] but minimally consists of four individual proteins: presenilin, nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2).Kaether C, Haass C, Steiner H. (2006). Assembly, trafficking and function of gamma-secretase. "Neurodegener Dis" 3(4-5):275-83. PMID 17047368] Recent evidence suggests that a fifth protein, known as CD147, is a non-essential regulator of the complex whose absence increases activity.Zhou S, Zhou H, Walian PJ, Jap BK. (2006). The discovery and role of CD147 as a subunit of gamma-secretase complex. "Drug News Perspect" 19(3):133-8. PMID 16804564 ] Zhou S, Zhou H, Walian PJ, Jap BK. (2005). CD147 is a regulatory subunit of the gamma-secretase complex in Alzheimer's disease amyloid beta-peptide production. "Proc Natl Acad Sci USA" 102(21):7499-504. PMID 15890777 ] Presenilin, an aspartyl protease, is the catalytic subunit; mutations in the presenilin gene have been shown to be a major genetic risk factor for Alzheimer's disease. In humans, two forms of presenilin and two forms of APH-1 have been identified in the genome; one of the APH homologs can also be expressed in two isoforms via alternative splicing, leading to at least six different possible gamma secretase complexes that may have tissue- or cell type specificity. Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H. (2004). Identification of distinct gamma-secretase complexes with different APH-1 variants. "J Biol Chem" 279(40):41340-5. PMID 15286082]

The proteins in the gamma secretase complex are heavily modified by proteolysis during assembly and maturation of the complex; a required activation step is in the autocatalytic cleavage of presenilin to N- and C-terminal fragments. Nicastrin's primary role is in maintaining the stability of the assembled complex and regulating intracellular protein trafficking.Zhang YW, Luo WJ, Wang H, Lin P, Vetrivel KS, Liao F, Li F, Wong PC, Farquhar MG, Thinakaran G, Xu H. (2005). Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components. "J Biol Chem" 280(17):17020-6. PMID 15711015 ] PEN-2 associates with the complex via binding of a transmembrane domain of presenilinWatanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T. (2005). Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1. "J Biol Chem" 280(51):41967-75. PMID 16234244 ] and, among other possible roles, helps to stabilize the complex after presenilin proteolysis has generated the activated N-terminal and C-terminal fragments.Prokop S, Shirotani K, Edbauer D, Haass C, Steiner H. (2004). Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. "J Biol Chem" 279(22):23255-61. PMID 15039426 ] APH-1, which is required for proteolytic activity, binds to the complex via a conserved alpha helix interaction motif and aids in initiating assembly of premature 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 ]

Cellular trafficking

The gamma secretase complex is thought to assemble and mature via proteolysis in the early endoplasmic reticulum.Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman MS, Haass C. (2005). Gamma-secretase complex assembly within the early secretory pathway. "J Biol Chem" 280(8):6471-8. PMID 15591316] The complexes are then transported to the late ER where they interact with and cleave their substrate proteins.Kim SH, Yin YI, Li YM, Sisodia SS. (2004). Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway."J Biol Chem" 279(47):48615-9. PMID 15456788] Gamma secretase complexes have also been observed localized to the mitochondria, where they may play a role in promoting apoptosis.Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE, Ito A, Winblad B, Cowburn RF, Thyberg J, Ankarcrona M. (2004). Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. 279(49):51654-60. PMID 15456764 ]


Gamma secretase is an internal protease that cleaves within the membrane-spanning domain of its substrate proteins, including amyloid precursor protein (APP) and Notch. Substrate recognition occurs via nicastrin ectodomain binding to the N-terminus of the target, which is then passed via a poorly understood process between the two presenilin fragments to a water-containing active site at which the catalytic aspartate residue resides. The active site must contain water to carry out hydrolysis within a hydrophobic environment in the interior of the cell membrane, although it is not well understood how water and proton exchange is effected, and as yet no X-ray crystallography structure of gamma secretase is available.Wolfe MS. (2006). The gamma-secretase complex: membrane-embedded proteolytic ensemble. "Biochemistry" 45(26):7931-9. PMID 16800619 ] Low-resolution electron microscopy reconstructions have allowed the visualization of the hypothesized internal pores of about 2 nanometres.Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. (2006). Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. "Proc Natl Acad Sci USA" 103(18):6889-94. PMID 16636269 ]

The gamma secretase complex is unusual among proteases in having a "sloppy" cleavage site at the C-terminal site in amyloid beta generation; gamma secretase can cleave APP in any of multiple sites to generate a peptide from 39 to 42 amino acids long, with Aβ40 the most common isoform and Aβ42 the most susceptible to conformational changes leading to amyloid fibrillogenesis. Certain mutations in both APP and in both types of human presenilin are associated with increased Aβ42 production and the early-onset genetic form of familial Alzheimer's disease.Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M. (2005). Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. "J Neurochem" 94(5):1189-201. PMID 15992373 ] Some evidence has suggested that different forms of the gamma secretase complex are differentially responsible for generating different amyloid beta isoforms;Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR. (2004). Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. "Hum Mol Genet" 13(2):159-70. PMID 14645205 ] however, very recent research indicates that the C-terminus of amyloid beta is produced by a series of single-residue cleavages by the same isoform, beginning with the generation of Aβ46.Zhao G, Tan J, Mao G, Cui MZ, Xu X. (2007). The same gamma-secretase accounts for the multiple intramembrane cleavages of APP. "J Neurochem" Epub. PMID 17241131]


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