The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase

Science. 2020 Sep 25;369(6511):eabc5809. doi: 10.1126/science.abc5809.

Michael J McKenna ¹, Sue Im Sim ², Alban Ordureau ¹, Lianjie Wei ¹, J Wade Harper ¹, Sichen Shao ³, Eunyong Park ⁴ ⁵

Affiliations

1 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
3 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. sichen_shao@hms.harvard.edu eunyong_park@berkeley.edu.
4 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. sichen_shao@hms.harvard.edu eunyong_park@berkeley.edu.
5 California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA.

PMID: 32973005 DOI: 10.1126/science.abc5809

Abstract

Organelle identity depends on protein composition. How mistargeted proteins are selectively recognized and removed from organelles is incompletely understood. Here, we found that the orphan P5A-adenosine triphosphatase (ATPase) transporter ATP13A1 (Spf1 in yeast) directly interacted with the transmembrane segment (TM) of mitochondrial tail-anchored proteins. P5A-ATPase activity mediated the extraction of mistargeted proteins from the endoplasmic reticulum (ER). Cryo-electron microscopy structures of Saccharomyces cerevisiae Spf1 revealed a large, membrane-accessible substrate-binding pocket that alternately faced the ER lumen and cytosol and an endogenous substrate resembling an α-helical TM. Our results indicate that the P5A-ATPase could dislocate misinserted hydrophobic helices flanked by short basic segments from the ER. TM dislocation by the P5A-ATPase establishes an additional class of P-type ATPase substrates and may correct mistakes in protein targeting or topogenesis.

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