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APP gamma-secretase

Function: - substrates of gamma-secretase include: - Notch 1-4 - APP - APLP1 & APLP2 - CD44 - erb B4 - LRP - E-cadherin - N-cadherin - the C99 & C83 peptides of the amyloid precursor protein (APP) appear to be incidental substrates of gamma-secretase [5] - removal of the ectodomain is required before gamma-secretase can cleave APP [7] - gamma-Secretase cleaves APP to form the C-terminus of the A4 peptide; there may be many sites of activity [1]; A4 peptides of 39-42 amino acid residues may be formed Structure: - core complex: - a presenilin homodimer (PSEN1 or PSEN2) - nicastrin (NCSTN) - APH1 (APH1A or APH1B) - PEN2 - other components associated with the core complex include - SLC25A64 - SLC5A7 - PHB - PSEN1 isoform 3 Compartment: - APP gamma-secretase may be active in endoplasmic reticulum, GOLGI, or within endosomes

Interactions

molecular events

General

aspartic proteinase; carboxyl acid protease molecular complex

Properties

STATE: active state MOTIF: active site MOTIF: aspartate residue (2) SUBUNITS: nicastrin MOTIF: signal sequence {1-33} N-glycosylation site {N45} N-glycosylation site {N55} N-glycosylation site {N187} N-glycosylation site {N200} N-glycosylation site {N204} N-glycosylation site {N264} N-glycosylation site {N387} N-glycosylation site {N417} N-glycosylation site {N435} N-glycosylation site {N464} N-glycosylation site {N506} N-glycosylation site {N530} N-glycosylation site {N562} N-glycosylation site {N573} N-glycosylation site {N580} N-glycosylation site {N612} transmembrane domain {670-690} presenilin-1 MOTIF: cytoplasmic domain {N-terminal} transmembrane domain {TM1} exoplasmic loop LOOP#: 1 transmembrane domain {TM2} cytoplasmic loop LOOP#: 1 transmembrane domain {TM3} exoplasmic loop LOOP#: 2 transmembrane domain {TM4} cytoplasmic loop LOOP#: 2 transmembrane domain {TM5} exoplasmic loop MOTIF: N-glycosylation site {exoplasmic loop [N279] } LOOP#: 3 transmembrane domain {TM6} MOTIF: aspartate residue {TM6} cytoplasmic loop MOTIF: proteolytic site {cytoplasmic loop LOOP#: 3} binding site SITE: cytoplasmic loop LOOP#: 3 FOR-BINDING-OF: catenin N-glycosylation site {N405} LOOP#: 3 transmembrane domain {TM7} MOTIF: aspartate residue {TM7} exoplasmic loop LOOP#: 4 transmembrane domain {TM8} cytoplasmic domain {C-terminal} pen-2 protein MOTIF: exoplasmic domain {1-17} transmembrane domain {18-38} cytoplasmic loop {39-60} transmembrane domain {61-81} exoplasmic domain {82-101} Aph-1 protein MOTIF: exoplasmic domain {N-TERMINAL} exoplasmic loop LOOP#: 1 exoplasmic loop LOOP#: 2 exoplasmic loop LOOP#: 3 transmembrane domain {TM1} transmembrane domain {TM2} transmembrane domain {TM3} transmembrane domain {TM4} transmembrane domain {TM5} transmembrane domain {TM6} transmembrane domain {TM7} cytoplasmic loop LOOP#: 1 cytoplasmic loop LOOP#: 2 cytoplasmic loop LOOP#: 3 cytoplasmic domain {C-TERMINAL}

References

  1. Ashall F, Goate AM. Role of the beta-amyloid precursor protein in Alzheimer's disease. Trends Biochem Sci. 1994 Jan;19(1):42-6. Review. PMID: 8140621
  2. Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000 Jun 8;405(6787):689-94. PMID: 10864326
  3. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000 Sep 7;407(6800):48-54. PMID: 10993067
  4. Marx J. Science 294:508, 2001
  5. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  6. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003 Mar 27;422(6930):438-41. Epub 2003 Mar 16. PMID: 12660785
  7. De Strooper B, Annaert W. Where Notch and Wnt signaling meet. The presenilin hub. J Cell Biol. 2001 Feb 19;152(4):F17-20. No abstract available. PMID: 11266476
  8. Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J. 2002 Oct 15;21(20):5408-16. PMID: 12374741
  9. Kimberly WT, Wolfe MS. Identity and function of gamma-secretase. J Neurosci Res. 74(3):353-60. 2003 Review. PMID: 14598311
  10. Wilson CA, Doms RW, Lee VM. Distinct presenilin-dependent and presenilin-independent gamma- secretases are responsible for total cellular Abeta production. J Neurosci Res. 74(3):361-9. 2003 Review. PMID: 14598312
  11. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003 Apr 10;38(1):9-12. Review. PMID: 12691659

Components

Aph-1 protein or homolog of C. elegans anterior pharynx defective 1 nicastrin (NCSTN, KIAA0253, UNQ1874/PRO4317) pen-2 protein; presenilin enhancer protein 2; gamma-secretase subunit pen-2 (PSENEN) presenilin-1; PS-1; EC=3.4.23.-; protein S182; contains: presenilin-1 NTF subunit; contains: presenilin-1 CTF subunit; contains: presenilin-1 CTF12; PS1-CTF12 (PSEN1, AD3, PS1, PSNL1)