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

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.

Automated summary

P5A- and P5B- ATPases, also known as P5-ATPases, are specific ATP-dependent transporters in eukaryotes that play important roles in the functions of the endoplasmic reticulum and endo-/lysosomes. Recent studies using cryo-electron microscopy and biochemistry have revealed the substrate specificities and transport mechanisms of P5-ATPases, which are distinct from other members of the P-type ATPase superfamily. P5A-ATPases are involved in protein quality control by extracting mistargeted or mis-inserted transmembrane helices from the ER membrane, while P5B-ATPases mediate the export of polyamines from late endo-/lysosomes to the cytosol. Structural analysis of yeast and human P5-ATPases has provided insights into their substrate recognition and transport mechanisms, highlighting the unique adaptation of the P5-ATPase subfamily for transporting atypical substrates.