Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules
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1
Memorial Sloan-Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, United States
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2
Weill Graduate School of Medical Sciences of Cornell University, Biochemistry and Molecular Biology Program, United States
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3
Weill Graduate School of Medical Sciences of Cornell University, Program of Pharmacology, United States
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4
Universiti Putra Malaysia, Department of Biomedical Science, Faculty of Medicine & Health Sciences, Malaysia
Gamma-secretase is a membrane-bound aspartyl-protease that cleaves many membrane substrates including Amyloid Precursor Protein (APP), Notch, E-cadherin, Her4 and CD44. APP is a particularly notable substrate because of its association with Alzheimer disease. Together, gamma-secretase and beta-secretase cleave APP to produce amyloid beta peptides that aggregate in the brain as cytotoxic beta-amlyoid plaques, which is one of the hallmarks of Alzheimer disease. Many small molecules are being developed to target gamma-secretase as a therapeutic strategy for Alzheimer disease. However, studying the effects of these molecules on the active site conformation of gamma-secretase is challenging due to the complexity of this enzyme. In our study, we have developed new biochemical techniques to probe the active site structure of gamma-secretase. We are able to show that different gamma-secretase inhibitors and modulators, when bind to gamma-secretase, affect the active site structure of gamma-secretase differently. More importantly, we discovered that these small molecules, which were developed to target gamma-secretase, also affect the active site structure of Signal Peptide Peptidase, a similar membrane-bound aspartyl-protease. This discovery has major implication on the development of gamma-secretase inhibitors as therapeutic drugs for Alzheimer disease due to potential off-target effects.
Keywords:
neurodegeneration,
Alzheimer’s disease,
therapeutic,
molecule,
Gamma secretase
Conference:
14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.
Presentation Type:
Poster Presentation Session
Topic:
14th Meeting of the Asian-Pacific Society for Neurochemistry
Citation:
Gertsik
N,
Li
Y and
Chau
D
(2016). Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules.
Conference Abstract:
14th Meeting of the Asian-Pacific Society for Neurochemistry.
doi: 10.3389/conf.fncel.2016.36.00137
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Received:
04 Aug 2016;
Published Online:
11 Aug 2016.
*
Correspondence:
Dr. De-Ming Chau, Universiti Putra Malaysia, Department of Biomedical Science, Faculty of Medicine & Health Sciences, Serdang, Selangor, Malaysia, chau.deming@gmail.com