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Reconstitution of γ‐secretase by truncated presenilin (PS) fragments revealed that PS C‐terminal transmembrane domain is critical for formation of γ‐secretase complex

The presenilin (PS) complex, including PS, nicastrin (NCT), APH‐1 and PEN‐2, is essential for γ‐secretase activity. Previously, the PS C‐terminal tail was shown to be essential for γ‐secretase activity. Here, to further understand the precise mechanism underlying the activation of γ‐secretase regulated by PS cofactors, we focused on the role of the PS1 C‐terminal region including transmembrane domain (TM) 8 in γ‐secretase activity. For this purpose, we co‐expressed C‐terminally truncated PS1 (PS1ΔC) completely lacking γ‐secretase activity and the PS1 C‐terminal short fragment in PS‐null cells, because the successful reconstitution of γ‐secretase activity in PS‐null cells by the co‐expression of PS1ΔC and the PS1 C‐terminal short fragment would allow us to investigate the role of the PS1 C‐terminal region in γ‐secretase activity. We found that the exogenous expression of the PS1 C‐terminal short fragment with NCT and APH‐1 completely rescued a defect of the γ‐secretase activity of PS1ΔC in PS‐null cells. With this reconstitution system, we demonstrate that both TM8 and the PS1 C‐terminal seven‐amino‐acid‐residue tail are involved in the formation of the active γ‐secretase complex via the assembly of PS1 with NCT and APH‐1.