TY - JOUR
T1 - Mutagenesis mapping of the presenilin 1 calcium leak conductance pore
AU - Nelson, Omar
AU - Supnet, Charlene
AU - Tolia, Alexandra
AU - Horre, Katrien
AU - De Strooper, Bart
AU - Bezprozvanny, Ilya
PY - 2011/6/24
Y1 - 2011/6/24
N2 - Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) proteins are a major cause of familial Alzheimer disease. Presenilins are proteins with nine transmembrane (TM) domains that function as catalytic subunits of the γ-secretase complex responsible for the cleavage of the amyloid precursor protein and other type I transmembrane proteins. The waterfilled cavity within presenilin is necessary to mediate the intramembrane proteolysis reaction. Consistent with this idea, cysteine-scanning mutagenesis and NMR studies revealed a number of water-accessible residues within TM7 and TM9 of mouse PS1. In addition to γ-secretase function, presenilins also demonstrate a low conductance endoplasmic reticulum Ca2+ leak function, and many familial Alzheimer disease presenilin mutations impair this function. To map the potential Ca2+ conductance pore in PS1, we systematically evaluated endoplasmic reticulum Ca2+ leak activity supported by a series of cysteine point mutants in TM6, TM7, and TM9 of mouse PS1. The results indicate that TM7 and TM9, but not TM6, could play an important role in forming the conductance pore of PS1. These results are consistent with previous cysteine-scanning mutagenesis and NMR analyses of PS1 and provide further support for our hypothesis that the hydrophilic catalytic cavity of presenilins may also constitute a Ca2+ conductance pore.
AB - Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) proteins are a major cause of familial Alzheimer disease. Presenilins are proteins with nine transmembrane (TM) domains that function as catalytic subunits of the γ-secretase complex responsible for the cleavage of the amyloid precursor protein and other type I transmembrane proteins. The waterfilled cavity within presenilin is necessary to mediate the intramembrane proteolysis reaction. Consistent with this idea, cysteine-scanning mutagenesis and NMR studies revealed a number of water-accessible residues within TM7 and TM9 of mouse PS1. In addition to γ-secretase function, presenilins also demonstrate a low conductance endoplasmic reticulum Ca2+ leak function, and many familial Alzheimer disease presenilin mutations impair this function. To map the potential Ca2+ conductance pore in PS1, we systematically evaluated endoplasmic reticulum Ca2+ leak activity supported by a series of cysteine point mutants in TM6, TM7, and TM9 of mouse PS1. The results indicate that TM7 and TM9, but not TM6, could play an important role in forming the conductance pore of PS1. These results are consistent with previous cysteine-scanning mutagenesis and NMR analyses of PS1 and provide further support for our hypothesis that the hydrophilic catalytic cavity of presenilins may also constitute a Ca2+ conductance pore.
UR - http://www.scopus.com/inward/record.url?scp=79959329917&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111.243063
DO - 10.1074/jbc.M111.243063
M3 - Article
C2 - 21531718
AN - SCOPUS:79959329917
SN - 0021-9258
VL - 286
SP - 22339
EP - 22347
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -