Structural insights into human signal peptide peptidase
- Gaoxingyu Huang
- Xuefei Guo
- Jiaoni Wang
- Xiaofei Ge
- Fang Kong
- Zilin Shen
- Xu Wang
- Chuangye Yan
- Jianlin Lei
- Yigong Shi
- Rui Zhou
2025-12-17
The signal peptide peptidase (SPP) remains the only intramembrane protease family that is yet to be structurally characterized. Here, we report the cryoelectron microscopy (cryo-EM) structures of human SPPL2a in two functional states: ligand-free and inhibitor-bound, at average resolutions of 3.3 and 3.6 Å, respectively. SPPL2a contains nine transmembrane helices with a conserved fold for the SPP and presenilin families. In the ligand-free state, an antiparallel β-hairpin is already formed near the active site, reminiscent of presenilin 1 (PS1) in its substrate-bound state. Binding by the small molecule inhibitor L685,458 triggers further conformational rearrangement in SPPL2a. Together with the cryo-EM structure of compound E-bound PS1, our findings reveal insights into selective inhibitor recognition and substrate gating by aspartyl intramembrane proteases. Structure-based sequence analysis unveils key differences between the SPP and presenilin families that underlie their function and assembly.