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Cell Rep. 2019 Apr 23;27(4):1221-1230.e3. doi: 10.1016/j.celrep.2019.03.106.

Structural Basis of Sarco/Endoplasmic Reticulum Ca2+-ATPase 2b Regulation via Transmembrane Helix Interplay.

Author information

1
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai 980-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Kawaguchi, Japan.
2
Graduate School of Biological Sciences, NARA Institute of Science and Technology, Ikoma 630-0192, Japan.
3
Graduate School of Biological Sciences, NARA Institute of Science and Technology, Ikoma 630-0192, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Kawaguchi, Japan.
4
Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
5
Institute for Protein Research, Osaka University, Suita 565-0871, Japan.
6
Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Kawaguchi, Japan.
7
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai 980-8577, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Kawaguchi, Japan. Electronic address: kinaba@tagen.tohoku.ac.jp.

Abstract

Sarco/endoplasmic reticulum (ER) Ca2+-ATPase 2b (SERCA2b) is a ubiquitously expressed membrane protein that facilitates Ca2+ uptake from the cytosol to the ER. SERCA2b includes a characteristic 11th 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 E1-2Ca2+-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.

KEYWORDS:

Ca(2+) homeostasis; Ca(2+)-ATPase; X-ray crystallography; endoplasmic reticulum; membrane protein

PMID:
31018135
DOI:
10.1016/j.celrep.2019.03.106
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