Effects of lipids on the activity and structural dynamics of gamma secretase: A study using coarse-grained molecular dynamics simulations

Abstract

Gamma secretase (GS) is an intramembranous enzyme that acts on the amyloid precursor protein and Notch inside lipid membranes. The enzyme is responsible for amyloid-β propagation, one of the well-known causes of Alzheimer's disease. However, the effects of lipids on GS activity and structural dynamics are unknown. Therefore, in this study, we performed coarse-grained molecular dynamics simulations to probe the effects of five individual lipids on GS. These lipids included 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl-sn-phosphatidylcholine (DOPC), 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC). These lipids are structurally characterized by different heads (i.e., NH₃ [PE] for POPE vs. NC₃ [PC] for POPC), number of double bonds (one for POPC vs. two for DOPC), and alkyl tail chain lengths (16:1/18:1 for DOPC vs. 14:0/14:0 for DMPC vs. 12:0/12:0 for DLPC). This indicates distinct microenvironments and adjustable structural elements for catalytic function when GS is embedded. Our results revealed that the presence of more unsaturated bonds in DOPC than in POPC resulted in greater GS stability. Moreover, lipids with short alkyl tail chains or with PC heads instead of PE heads had improved mobility of the sixth transmembrane helix of GS, which is responsible for the considerable active site flexibility and presenilin 1 subunit plasticity. The length of the DMPC alkyl tail chain was between that of DOPC and DLPC because the up-down and cross-correlation motions of GS in DMPC was the lowest among the three lipids, and GS mobility in DMPC was the lowest among all five lipids. This may be because the alkyl tail chain length (i.e., 3. 8 nm thickness of the DMPC bilayer) was suitable for GS embedding, thereby restraining more GS motions than that of the long (DOPC) or short lipids (DLPC). Collectively, these results indicated that GS activity can be modulated through changes in conformational fluctuations, structural perturbations, molecular motion, and cross-correlation motion when embedded in different lipids. Exploration of such fundamental information can reveal the possible mechanisms by which GS is affected by individual lipid species.

Keywords

Five lipids / Gamma secretase / Presenilin / Nicastrin / Effect of lipid on GS

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Ahmad Sajjad: Writing - original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Jinfei Mei: Methodology, Investigation, Formal analysis. Chuanbo Wang: Methodology, Investigation, Formal analysis. Hongqi Ai: Writing - review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Acknowledgements

This study was supported by Shandong Provincial Natural Science Foundation of China (ZR2022MB073).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.chphma.2024.03.005.

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