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ATP13A1 engages SEC61 to facilitate substrate-specific translocation
Xiaoyan Yang1,2, Yi Li1, Chengxi Yang1
1School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Science Advances
|June 11, 2025
Summary
This study reveals how atypical signal sequences are recognized and reverse-targeted to the endoplasmic reticulum. The P5A-ATPase ATP13A1 then dislocates these sequences for proper protein localization.
Area of Science:
- Cell Biology
- Molecular Biology
- Protein Trafficking
Background:
- Accurate protein targeting is crucial for cellular function.
- Variable signal sequences in secreted/membrane proteins challenge precise localization within the secretory pathway.
Purpose of the Study:
- To investigate the mechanism of atypical signal sequence recognition and translocation.
- To elucidate the role of ATP13A1 in misoriented signal sequence processing.
Main Methods:
- Cryo-electron microscopy of human ATP13A1.
- Structural analysis of ATP13A1 conformations.
- Biochemical assays to study signal sequence interactions.
Main Results:
- Atypical signal sequences are recognized by signal recognition particle and reverse-targeted to the ER.
- P5A-ATPase ATP13A1 dislocates misoriented signal sequences.
- ATP13A1 structure reveals key residues interacting with signal sequences via polar interactions.
Conclusions:
- A novel translocation pathway for atypical signal sequences is elucidated.
- This pathway ensures efficient and accurate protein subcellular localization.
- Findings provide insights into maintaining cellular architecture and function.
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