Crump Christina J, Fish Benjamin A, Castro Suita V, Chau De-Ming, Gertsik Natalya, Ahn Kwangwook, Stiff Cory, Pozdnyakov Nikolay, Bales Kelly R, Johnson Douglas S, Li Yue-Ming
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
ACS Chem Neurosci. 2011 Dec 21;2(12):705-710. doi: 10.1021/cn200098p.
Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.
β淀粉样蛋白42（Aβ42）被认为在阿尔茨海默病（AD）发病机制中起致病作用。γ-分泌酶调节剂（GSMs）正作为潜在的AD治疗药物而被积极研究，因为它们能选择性地改变淀粉样前体蛋白（APP）的切割位点，以减少Aβ42的形成。然而，基于酸的GSMs的结合伴侣至今仍未明确。我们基于哌啶乙酸GSM-1开发了可点击的光亲和探针，并确定早老素1（PS1）是γ-分泌酶复合物中的靶点。此外，我们提供的证据表明，GSMs与PS1的变构相互作用导致γ-分泌酶复合物活性位点的构象变化，从而引起所观察到的γ-分泌酶活性调节。
