Journal article

Transition-state analogue gamma-secretase inhibitors stabilize a 900 kDa presenilin/nicastrin complex

G Evin, LD Canterford, DE Hoke, RA Sharples, JG Culvenor, CL Masters

Biochemistry | AMER CHEMICAL SOC | Published : 2005


Gamma-secretase mediates the final step, which generates Alzheimer's disease Abeta amyloid protein, by cleaving the transmembrane domain of the amyloid-beta protein precursor. Four gene products, presenilin, nicastrin, APH-1, and PEN-2, are required for gamma-secretase activity that is contained within a high molecular mass complex. To further characterize gamma-secretase, we probed membranes from human neuroblastoma SH-SY5Y cells with gamma-secretase inhibitor biotin derivatives of L-685,458, pepstatin A, and the difluoro alcohol 1-Bt. These inhibitor derivatives bound and precipitated PS1 fragments from membrane CHAPSO extracts. Analysis of PS1 complexes by blue native gel electrophoresis ..

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