Structural Basis of Sarco/Endoplasmic Reticulum Ca 2+ -ATPase 2b Regulation via Transmembrane Helix Interplay

Michio Inoue, Nanami Sakuta, Satoshi Watanabe, Yuxia Zhang, Kunihito Yoshikaie, Yoshiki Tanaka, Ryo Ushioda, Yukinari Kato, Junichi Takagi, Tomoya Tsukazaki, Kazuhiro Nagata, Kenji Inaba

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9 Citations (Scopus)

Abstract

Sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2b (SERCA2b) is a ubiquitously expressed membrane protein that facilitates Ca 2+ uptake from the cytosol to the ER. SERCA2b includes a characteristic 11 th transmembrane helix (TM11) followed by a luminal tail, but the structural basis of SERCA regulation by these C-terminal segments remains unclear. Here, we determined the crystal structures of SERCA2b and its C-terminal splicing variant SERCA2a, both in the E1-2Ca 2+ -adenylyl methylenediphosphonate (AMPPCP) state. Despite discrepancies with the previously reported structural model of SERCA2b, TM11 was found to be located adjacent to TM10 and to interact weakly with a part of the L8/9 loop and the N-terminal end of TM10, thereby inhibiting the SERCA2b catalytic cycle. Accordingly, mutational disruption of the interactions between TM11 and its neighboring residues caused SERCA2b to display SERCA2a-like ATPase activity. We propose that TM11 serves as a key modulator of SERCA2b activity by fine-tuning the intramolecular interactions with other transmembrane regions.

Original languageEnglish
Pages (from-to)1221-1230.e3
JournalCell Reports
Volume27
Issue number4
DOIs
Publication statusPublished - 2019 Apr 23

Keywords

  • Ca -ATPase
  • Ca homeostasis
  • X-ray crystallography
  • endoplasmic reticulum
  • membrane protein

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Inoue, M., Sakuta, N., Watanabe, S., Zhang, Y., Yoshikaie, K., Tanaka, Y., Ushioda, R., Kato, Y., Takagi, J., Tsukazaki, T., Nagata, K., & Inaba, K. (2019). Structural Basis of Sarco/Endoplasmic Reticulum Ca 2+ -ATPase 2b Regulation via Transmembrane Helix Interplay Cell Reports, 27(4), 1221-1230.e3. https://doi.org/10.1016/j.celrep.2019.03.106