TY - JOUR
T1 - Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid β peptide length
T2 - Support for a sequential model of γ-secretase intramembrane proteolysis and regulation by the amyloid β precursor protein (APP) juxtamembrane region
AU - Kukar, Thomas L.
AU - Ladd, Thomas B.
AU - Robertson, Paul
AU - Pintchovski, Sean A.
AU - Moore, Brenda
AU - Bann, Maralyssa A.
AU - Ren, Zhao
AU - Jansen-West, Karen
AU - Malphrus, Kim
AU - Eggert, Simone
AU - Maruyama, Hiroko
AU - Cottrell, Barbara A.
AU - Das, Pritam
AU - Basi, Guriqbal S.
AU - Koo, Edward H.
AU - Golde, Todd E.
PY - 2011/11/18
Y1 - 2011/11/18
N2 - γ-Secretase is a multiprotein intramembrane cleaving aspartyl protease (I-CLiP) that catalyzes the final cleavage of the amyloid β precursor protein (APP) to release the amyloid β peptide (Aβ). Aβ is the primary component of senile plaques in Alzheimer's disease (AD), and its mechanism of production has been studied intensely. γ-Secretase executes multiple cleavages within the transmembrane domain of APP, with cleavages producing Aβ and the APP intracellular domain (AICD), referred to as γ and ε, respectively. The heterogeneous nature of the γ cleavage that produces various Aβ peptides is highly relevant to AD, as increased production of Aβ 1-42 is genetically and biochemically linked to the development of AD. We have identified an amino acid in the juxta membrane region of APP, lysine 624, on the basis of APP695 numbering (position 28 relative to Aβ) that plays a critical role in determining the final length of Aβ peptides released by γ-secretase. Mutation of this lysine to alanine (K28A) shifts the primary site of γ-secretase cleavage from 1-40 to 1-33 without significant changes to ε cleavage. These results further support a model where ε cleavage occurs first, followed by sequential proteolysis of the remaining transmembrane fragment, but extend these observations by demonstrating that charged residues at the luminal boundary of the APP transmembrane domain limit processivity of γ-secretase.
AB - γ-Secretase is a multiprotein intramembrane cleaving aspartyl protease (I-CLiP) that catalyzes the final cleavage of the amyloid β precursor protein (APP) to release the amyloid β peptide (Aβ). Aβ is the primary component of senile plaques in Alzheimer's disease (AD), and its mechanism of production has been studied intensely. γ-Secretase executes multiple cleavages within the transmembrane domain of APP, with cleavages producing Aβ and the APP intracellular domain (AICD), referred to as γ and ε, respectively. The heterogeneous nature of the γ cleavage that produces various Aβ peptides is highly relevant to AD, as increased production of Aβ 1-42 is genetically and biochemically linked to the development of AD. We have identified an amino acid in the juxta membrane region of APP, lysine 624, on the basis of APP695 numbering (position 28 relative to Aβ) that plays a critical role in determining the final length of Aβ peptides released by γ-secretase. Mutation of this lysine to alanine (K28A) shifts the primary site of γ-secretase cleavage from 1-40 to 1-33 without significant changes to ε cleavage. These results further support a model where ε cleavage occurs first, followed by sequential proteolysis of the remaining transmembrane fragment, but extend these observations by demonstrating that charged residues at the luminal boundary of the APP transmembrane domain limit processivity of γ-secretase.
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U2 - 10.1074/jbc.M111.274696
DO - 10.1074/jbc.M111.274696
M3 - Article
C2 - 21868378
AN - SCOPUS:81155154306
SN - 0021-9258
VL - 286
SP - 39804
EP - 39812
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 46
ER -