Evidence That the "lid" domain of nicastrin is not essential for regulating γ-secretase activity Journal Article
| Authors: | Zhang, X.; Sullivan, E.; Scimeca, M.; Wu, X.; Li, Y. M.; Sisodia, S. S. |
| Article Title: | Evidence That the "lid" domain of nicastrin is not essential for regulating γ-secretase activity |
| Abstract: | Understanding of the structure of the γ-secretase complex consisting of presenilin (PS), anterior pharynx-defective 1 (APH-1), nicastrin (NCT), and presenilin enhancer 2 (PEN-2) is of significant therapeutic interest for the design of γ-secretase modulators for Alzheimer disease. The structure of γ-secretase revealed by cryo-EM approaches suggested a substrate binding mechanism for NCT, a bilobar structure that involved rotation of the two lobes around a central pivot and opening of a "lid" region that facilitates substrate recruitment. To validate this proposal, we expressed NCT that lacks the lid entirely, or a variety of NCT variants that harbor mutations at highly conserved residues in the lid region in NCT-deficient cells, and then assessed their impact on γ-secretase assembly, activity, and stability. In addition, we assessed the impact of mutating a critical residue proposed to be a pivot around which the two lobes of NCTrotate. Our results show that neither the mutations on the lid tested here nor the entire lid deletion has any significant impact on γ-secretase assembly, activity, and stability, and thatNCTwith the mutation of the proposed pivot rescues γ-secretase activity in NCT-deficient cells in a manner indistinguishable fromWTNCT. These findings indicate that theNCTlid is not an essential element necessary for γ-secretase assembly, activity, and stability, and that rotation of the two lobes appears not to be a prerequisite for substrate binding andγ-secretase function. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | medical imaging; alzheimer disease; presenilins; secretase complex; secretases; conserved residues; bins; substrate binding; essential elements; substrate-binding mechanism |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 291 |
| Issue: | 13 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2016-03-25 |
| Start Page: | 6748 |
| End Page: | 6753 |
| Language: | English |
| DOI: | 10.1074/jbc.C115.701649 |
| PROVIDER: | scopus |
| PMCID: | PMC4807262 |
| PUBMED: | 26887941 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2016 -- Source: Scopus |
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