The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H+-ATPase biogenesis

Kenichiro Kinouchi, Atsuhiro Ichihara, Motoaki Sano, Ge Hong Sun-Wada, Yoh Wada, Hiroki Ochi, Toru Fukuda, Kanako Bokuda, Hideaki Kurosawa, Naohiro Yoshida, Shu Takeda, Keiichi Fukuda, Hiroshi Itoh

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The ATPase 6 accessory protein 2 (ATP6AP2)/(pro)renin receptor (PRR) is essential for the biogenesis of active vacuolar H+-ATPase (V-ATPase). Genetic deletion of ATP6AP2/PRR causes V-ATPase dysfunction and compromises vesicular acidification. Here, we characterized the domains of ATP6AP2/PRR involved in active V-ATPase biogenesis. Three forms of ATP6AP2/PRR were found intracellularly: full-length protein and the N- and C-terminal fragments of furin cleavage products, with the Nterminal fragment secreted extracellularly. Genetic deletion of ATP6AP2/PRR did not affect the protein stability of V-ATPase subunits. The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2/PRR were indispensable for the biogenesis of active V-ATPase. A deletion mutant of ATP6AP2/PRR, which lacks exon 4-encoded amino acids inside the ECD (Δ4M) and causes X-linked mental retardation Hedera type (MRXSH) and X-linked parkinsonism with spasticity (XPDS) in humans, was defective as a V-ATPase-associated protein. Prorenin had no effect on the biogenesis of active V-ATPase. The cleavage of ATP6AP2/PRR by furin seemed also dispensable for the biogenesis of active V-ATPase. We conclude that the N-terminal ECD of ATP6AP2/PRR, which is also involved in binding to prorenin or renin, is required for the biogenesis of active V-ATPase. The V-ATPase assembly occurs prior to its delivery to the trans-Golgi network and hence shedding of ATP6AP2/PRR would not affect the biogenesis of active V-ATPase.

Original languageEnglish
Article numbere78603
JournalPloS one
Volume8
Issue number11
DOIs
Publication statusPublished - 2013 Nov 4

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Kinouchi, K., Ichihara, A., Sano, M., Sun-Wada, G. H., Wada, Y., Ochi, H., Fukuda, T., Bokuda, K., Kurosawa, H., Yoshida, N., Takeda, S., Fukuda, K., & Itoh, H. (2013). The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H+-ATPase biogenesis. PloS one, 8(11), [e78603]. https://doi.org/10.1371/journal.pone.0078603