Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes.
gamma-Secretase is known to play a pivotal role in the pathogenesis of Alzheimer disease through production of amyloidogenic Abeta42 peptides. Early onset familial Alzheimer disease mutations in presenilin (PS), the catalytic core of gamma-secretase, invariably increase the Abeta42:Abeta40 ratio. However, the mechanism by which these mutations affect gamma-secretase complex formation and cleavage specificity is poorly understood. We show that our in vitro assay system recapitulates the effect of PS1 mutations on the Abeta42:Abeta40 ratio observed in cell and animal models. We have developed a series of small molecule affinity probes that allow us to characterize active gamma-secretase complexes. Furthermore we reveal that the equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Abeta42:Abeta40 ratios. These data suggest that perturbations to gamma-secretase complex equilibrium can have a profound effect on enzyme activity and that increased PS2 complexes along with mutated PS1 complexes contribute to an increased Abeta42:Abeta40 ratio.
Placanica
Lisa
L
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065; Department of Pharmacology, Weill Graduate School of Medical Science of Cornell University, New York, New York 10065.
Tarassishin
Leonid
L
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Yang
Guangli
G
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Peethumnongsin
Erica
E
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
Kim
Seong-Hun
SH
The Center for Molecular Neurobiology, The University of Chicago, Chicago, Illinois 60637.
Zheng
Hui
H
Huffington Center on Aging, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
Sisodia
Sangram S
SS
The Center for Molecular Neurobiology, The University of Chicago, Chicago, Illinois 60637.
Li
Yue-Ming
YM
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065; Department of Pharmacology, Weill Graduate School of Medical Science of Cornell University, New York, New York 10065. Electronic address: liy2@mskcc.org.
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001710:Biotin / Q000378:metabolism; D002460:Cell Line; D005182:Flavin-Adenine Dinucleotide / Q000235:genetics / Q000502:physiology; D055879:Gene Knock-In Techniques; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D053764:Presenilin-1 / Q000378:metabolism / Q000502:physiology*; D053766:Presenilin-2 / Q000378:metabolism / Q000502:physiology*
D008565:Membrane Proteins; C508861:PSEN2 protein, human; C469349:PSENEN protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D005182:Flavin-Adenine Dinucleotide; D001710:Biotin; D053829:Amyloid Precursor Protein Secretases