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

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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

Vacuolar Proton-Translocating ATPases
renin
H-transporting ATP synthase
Accessories
Renin
adenosinetriphosphatase
Adenosine Triphosphatases
receptors
Proteins
proteins
Furin
biogenesis
Hedera
X-Linked Mental Retardation
trans-Golgi Network
Acidification
Protein Stability
Parkinsonian Disorders
Protein C
acidification

ASJC Scopus subject areas

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

Cite this

The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H+-ATPase biogenesis. / Kinouchi, Kenichiro; Ichihara, Atsuhiro; Sano, Motoaki; Sun-Wada, Ge Hong; Wada, Yoh; Ochi, Hiroki; Fukuda, Toru; Bokuda, Kanako; Kurosawa, Hideaki; Yoshida, Naohiro; Takeda, Shu; Fukuda, Keiichi; Itoh, Hiroshi.

In: PLoS One, Vol. 8, No. 11, e78603, 04.11.2013.

Research output: Contribution to journalArticle

Kinouchi, K, Ichihara, A, Sano, M, Sun-Wada, GH, 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, vol. 8, no. 11, e78603. https://doi.org/10.1371/journal.pone.0078603
Kinouchi, Kenichiro ; Ichihara, Atsuhiro ; Sano, Motoaki ; Sun-Wada, Ge Hong ; Wada, Yoh ; Ochi, Hiroki ; Fukuda, Toru ; Bokuda, Kanako ; Kurosawa, Hideaki ; Yoshida, Naohiro ; Takeda, Shu ; Fukuda, Keiichi ; Itoh, Hiroshi. / The role of individual domains and the significance of shedding of ATP6AP2/(pro)renin receptor in vacuolar H+-ATPase biogenesis. In: PLoS One. 2013 ; Vol. 8, No. 11.
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