γ-Secretase is a multi-subunit protein complex that is composed of at least four proteins-Presenilin (PS), Nicastrin (Net), Presenilin-enhancer 2 (Pen2) and Anteriorpharyx defective (Aph). These four subunits form an active γ-Secretase complex in the cell to regulate many cellular processes including Notch signaling. In this role, γ-Secretase cleaves Notch to release Notch intracellular domain (NICD), which translocates into the nucleus to act as a transcription coactivator. The role of Notch signaling is cell-specific and context-dependent. Studies showed that Notch signaling regulates embryonic stem cell differentiation, hematopoietic stem cell renewal and neural progenitor cell maintenance. Aberrant Notch signaling has been implicated in many cancers such as leukemia, glioma, and breast cancer. In addition to catalyzing the cleavage of Notch, γ-Secretase also cleaves amyloid precursor protein (APP) as well as many other substrates. γ-Secretase cleavage of APP generates β-amyloid peptides (Aβ) that aggregate in the brain to form amyloid plaques. The amyloid cascade hypothesis has suggested that the accumulation of amyloid plaques is one of the hallmarks of Alzheimer’s disease (AD). Since γ-Secretase regulates normal cellular functions and deregulate γ-Secretase processing of substrate has been associated with AD and cancers, it is essential to better understand how γ-Secretase is regulated.
Since γ-Secretase is a multi-subunit protein complex and each component is required for functionality, it has been challenging to obtain an X-ray crystal structure of the γ-Secretase complex. Recently, the structure of γ-Secretase was determined by cryoEM at a resolution of 12A. The cryo-EM structure shows three small individual low-density interior regions that might form water chambers within γ-Secretase to allow catalysis of substrates within the water-impermeable transmembrane region. Also, the cryo-EM structure shows the overall size of the complex to be ~ 8-10nm, which is consistent with a previous EM study. The resolution of the cryo-EM structure is insufficient to provide detailed analysis on the precise structure of γ-Secretase and its active site.
To date, several γ-Secretase inhibitors have been reported including L-685,458, Compound E, and DAPT. These inhibitors block the cleavage of APP and other substrates including Notch, and have toxic effects when administered in animal models. To overcome this toxic effect, a new class of compounds known as γ-Secretase modulators was developed that included CS-1 and derivatives of non-steroidal anti- inflammatory drugs. These compounds selectively reduce the level of Aβ42 while exhibiting a diminished inhibition of Aβ40 and NICD, however, the effectiveness of these compounds in treating AD in humans remains unknown. In addition to developing γ-Secretase inhibitors for AD, γ-Secretase has also been targeted for cancer therapy through the inhibition of Notch cleavage. RO4929097 is a γ-Secretase inhibitor that can selectively inhibit Notch cleavage, but this compound is only ~4 fold more selective. Therefore, extensive drug discovery efforts are required to develop selective γ-Secretase inhibitors targeting either APP or Notch cleavage that can be used for AD and cancer treatment.
De-Ming Chau. Biochemical and Pharmacological Study of γ-Secretase in Alzheimer’s Disease and Cancer