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1.  Deducing the transmembrane domain organization of presenilin-1 in γ-secretase by cysteine disulfide crosslinking† 
Biochemistry  2006;45(24):7598-7604.
γ-Secretase is a founding member of membrane-embedded aspartyl proteases that cleave substrates within transmembrane domains, and this enzyme is an important target for the development of therapeutics for Alzheimer’s disease. The structure of γ-secretase and its precise catalytic mechanism still remain largely unknown. γ-Secretase is a complex of four integral membrane proteins, with presenilin (PS) as the catalytic component. To gain structural and functional information about the 9-transmembrane domain (TMD) presenilin, we employed a cysteine mutagenesis/disulfide-crosslinking approach. Here we report that native Cys92 is close to both Cys410 and Cys419, strongly implying that TMD1 and TMD8 are adjacent to each other. This structural arrangement also suggests that TMD8 is distorted from an ideal helix. Importantly, binding of an active-site directed inhibitor, but not a docking-site directed inhibitor, reduces the ability of the native cysteine pairs of PS1 to crosslink upon oxidation. These findings suggest that the conserved cysteines of TMD1 and TMD8 contribute to or allosterically interact with the active site of γ-secretase.
PMCID: PMC2597485  PMID: 16768455

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