P5-ATPases: Structure, substrate specificities, and transport mechanisms

Curr Opin Struct Biol. 2023 Apr:79:102531. doi: 10.1016/j.sbi.2023.102531. Epub 2023 Jan 30.

Abstract

P5A- and P5B- ATPases, or collectively P5-ATPases, are eukaryotic-specific ATP-dependent transporters that are important for the function of the endoplasmic reticulum (ER) and endo-/lysosomes. However, their substrate specificities had remained enigmatic for many years. Recent cryo-electron microscopy (cryo-EM) and biochemical studies of P5-ATPases have revealed their substrate specificities and transport mechanisms, which were found to be markedly different from other members of the P-type ATPase superfamily. The P5A-ATPase extracts mistargeted or mis-inserted transmembrane helices from the ER membrane for protein quality control, while the P5B-ATPases mediate export of polyamines from late endo-/lysosomes into the cytosol. In this review, we discuss the mechanisms of their substrate recognition and transport based on the cryo-EM structures of the yeast and human P5-ATPases. We highlight how structural diversification of the transmembrane domain has enabled the P5-ATPase subfamily to adapt for transport of atypical substrates.

Keywords: Endoplasmic reticulum; Kufor Rakeb syndrome; Lysosomes; P-type ATPases; P5-ATPases; Parkinson's disease; Polyamine; Protein quality control; Tail-anchored membrane proteins.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphatases* / chemistry
  • Cryoelectron Microscopy
  • Endoplasmic Reticulum* / metabolism
  • Humans
  • Protein Domains
  • Saccharomyces cerevisiae / metabolism
  • Substrate Specificity

Substances

  • Adenosine Triphosphatases