The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase

Science. 2020 Sep 25;369(6511):eabc5809. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Binding Cassette Transporters / chemistry*
  • Cryoelectron Microscopy
  • Endoplasmic Reticulum / enzymology*
  • HeLa Cells
  • Humans
  • Mitochondrial Membranes / enzymology*
  • P-type ATPases / chemistry*
  • P-type ATPases / genetics
  • Protein Conformation, alpha-Helical
  • Protein Domains
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Sequence Alignment

Substances

  • ATP-Binding Cassette Transporters
  • SPF1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • ATP13A1 protein, human
  • P-type ATPases