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Sci Rep. 2016 Sep 27;6:34174. doi: 10.1038/srep34174.

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter.

Shao J1,2, Fu Z3,4, Ji Y1,2, Guan X1, Guo S1, Ding Z3,4, Yang X1, Cong Y3,4, Shen Y1,2,5.

Author information

1
State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China.
2
College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
3
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201210, China.
4
Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
5
Synergetic Innovation Center of Chemical Science and Engineering, 94 Weijin Road, Tianjin 300071, China.

Abstract

Leucine zipper-EF-hand-containing transmembrane protein1 (LETM1) is located in the mitochondrial inner membrane and is defective in Wolf-Hirschhorn syndrome. LETM1 contains only one transmembrane helix, but it behaves as a putative transporter. Our data shows that LETM1 knockdown or overexpression robustly increases or decreases mitochondrial Ca2+ level in HeLa cells, respectively. Also the residue Glu221 of mouse LETM1 is identified to be necessary for Ca2+ flux. The mutation of Glu221 to glutamine abolishes the Ca2+-transport activity of LETM1 in cells. Furthermore, the purified LETM1 exhibits Ca2+/H+ anti-transport activity, and the activity is enhanced as the proton gradient is increased. More importantly, electron microscopy studies reveal a hexameric LETM1 with a central cavity, and also, observe two different conformational states under alkaline and acidic conditions, respectively. Our results indicate that LETM1 is a Ca2+/H+ antiporter and most likely responsible for mitochondrial Ca2+ output.

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