Introduction: the generation of beta amyloid by presenilin and its binding proteins 1 2 1 3 1 1 ε ζ 4 7 4 7 8 9 Fig 1 1–40 1–42 165  10 11 12 13 17 13 18 15 19 24 25 27 The roles of presenilin and its binding partners within the γ-secretase complex in Aβ generation  Presenilin 1: the catalytic component of the γ-secretase enzyme 28 30 31 34 35 37 38 40 41 42 43 44 45 46 47 12 48 51 52 53 54 Nicastrin: the substrate docking site and scaffolding for building the γ-secretase complex 55 55 14 56 58 14 55 59 61 1 62 63 63 64 Anterior pharynx defective 1 (aph-1): scaffolding partner for nicastrin and may have possible catalytic activity 65 19 21 66 67 66 67 66 21 68 69 1 24 70 68 11 19 24 71 68 72 72 68 73 Presenilin Enhancer 2 (pen-2): the elusive presenilinase or “molecular clamp” that holds the complex together? 74 75 76 77 15 19 22 24 11 22 24 27 71 24 70 1 78 80 78 78 81 The newest member of the complex: TMP21, a modulator of γ-secretase activity 82 83 84 82 ε 82 Presenilin 2 (PS2): capable of forming a fully functional γ-secretase complex 85 86 33 87 90 89 91 91 91 92 93 93 The roles of presenilin binding proteins not incorporated into the active γ-secretase complex 1 1 2 Table 1 Presenilin interacting proteins Interacting protein Proposed function Interaction with presenilins shown to modulate Aβ production  Reference Complex components APH-1 Component of the γ-secretase complex; role for initial formation of the complex, or a proteolytic role Yes 19 65 67 123 Nicastrin Component of γ-secretase complex; possible role as a receptor for APP-C99 Yes 14 55 58 PEN-2 Component of the γ-secretase complex, role in proteolytic cleavage of the presenilins  Yes  19 24 70 76 77 TMP21 Recently identified component of the γ-secretase complex, role in modulating Aβ production Yes 82 γ-secretase substrates APP-C99 Substrate for the γ-secretase complex: precursor to Aβ generation Yes  38 40 E/N cadherin γ-secretase substrate; role in Cell-Cell Adhesion No 124 IRE1 γ-secretase substrate; role in unfolded protein response No 125 126 LRP γ-secretase substrate; Lipid metabolism Yes  119 Notch1  γ-secretase substrate; precursor to NICD generation Yes  112 Interacting binding proteins ABP-280, Filamin homolog1 Actin binding protein No 127 Bcl-2  Anti-apoptotic molecule No 128 L Anti-apoptotic molecule No 129 Calmyrin Possible calcium-myrstol switch No 130 CALP- calsenilin like protein Novel member of the calsenilin/KChIp protein family No 131 Calsenilin Calcium binding protein Yes 94 96 99 101 102 CLIP-170 Linking membrane organelles to microtubules  No 132 DRAL LIM-domain containing protein No 133 FHL2 Role in PI3K/Akt activation No 134 FKBP38 Role in mitochondria mediated apoptosis  No 135 Go Signalling molecule No 136 GSK3β Wnt signalling, serine threonine protein kinase  No 137 HC5/ZETA Subunits of the catalytic 20S proteasome Yes 138 Met1 Putative methyltransferase No 139 Modifier of cell adhesion protein (MOCA) Regulates proteasomal activity on APP Yes 140 Omi/HtrA2 Serine protease, proapoptotic No 141 PAG Neuronal proliferation protein No 142 PAMP and PARL Metalloproteases  No 143 PKA Serine/Theronine protein kinase; β-catenin phosphorylation No 144 Plakoglobin Role in b-catenin/Tcf-4 activity No 145 PLD1 Phospholipid-modifying enzyme Yes  146 PSAP PDZ like protein No 147 QM/Jif1 Negative regulator of c-Jun No 148 Rab proteins Vesicle mediated protein trafficking Yes 149 150 RyR2 Cardiac ryanodine receptor  No 151 SEL-10 Ubiquitination of proteins Yes 152 Sorcin Calcium binding regulator of ryanodine receptor No 153 Syntaxin 1A Synaptic plasma-membrane protein No 154 Syntaxin 5 ER-Golgi vesicular transport Yes 155 156 Tau Microtubule binding protein No 137 Telencephalin Neuron specific adhesion molecule No 40 TPIP Tetratricopeptide repeat-containing protein No 157 Ubiquilin Ubiquitin domain-containing protein No 158 160 X11 family of proteins Cytoplasmic adaptor proteins Yes 110 111 β-catenin/δ-catenin (NPARP) Wnt signalling. Cell adhesion No 161 163 μ-Calpain Calcium-dependent thiol protease No 164 Fig. 2 A B A B  Calsenilin 94 95 96 97 98 99 100 18 101 102 X11/Mint proteins 103 106 103 106 109 103 106 109 110 111 Competing substrates 112 115 116 116 117 118 119 119 Taken together, these studies not only suggest substrate competition but also the presence of a single γ-secretase. However, the presence of multiple γ-secretase complexes cannot be ruled out. As discussed above there is evidence in the literature for the formation of γ-secretase complexes with distinct functions. All of the studies described above are undertaken in conditions where there is a large amount of substrate available which could down-regulate the activity of one γ-secretase for another. Whether substrate competition occurs under physiological conditions and if there are certain conditions that promote a higher expression of one substrate over another remains to be determined. Concluding comments 120 121 122