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FASEB J. 2019 Feb 20:fj201802182R. doi: 10.1096/fj.201802182R. [Epub ahead of print]

Maspin binds to cardiolipin in mitochondria and triggers apoptosis.

Author information

1
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
2
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
3
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
4
Faculty of Pharmaceutical Sciences, Doshisha Women's University, Kyoto, Japan.
5
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Abstract

A central question in cell biology is how cells respond to stress signals and biochemically regulate apoptosis. One critical pathway involves the change of mitochondrial function and release of cytochrome c to initiate apoptosis. In response to apoptotic stimuli, we found that maspin-a noninhibitory member of the serine protease inhibitor superfamily-translocates from the cytosol to mitochondria and binds to cardiolipin in the inner mitochondrial membrane. Biolayer interferometry assay revealed that recombinant maspin binds cardiolipin with an apparent Kd,of ∼15.8 μM and competes with cytochrome c (apparent Kd of ∼1.31 μM) for binding to cardiolipin-enriched membranes. A hydrophobic, lysine-rich domain in maspin consists of 27 aa, is located at position 268-294, and is responsible for the interaction of this protein with cardiolipin. Depletion of cardiolipin in cells significantly prevents maspin binding to the inner mitochondrial membrane and decreases cytochrome c release and apoptosis. Alteration to maspin's cardiolipin binding domain changes its ability to bind cardiolipin, and tumor cells expressing this mutant have a low frequency of apoptosis. We propose a model of apoptosis in which maspin binds to cardiolipin, displaces cytochrome c from the membrane, and facilitates its release to the cytoplasm.-Mahajan, N., Hoover, B., Rajendram, M., Shi, H. Y., Kawasaki, K., Weibel, D. B., Zhang, M. Maspin binds to cardiolipin in mitochondria and triggers apoptosis.

KEYWORDS:

anionic phospholipids; cytochrome ; diphosphatidylglycerol; mitochondrial membranes

PMID:
30786218
DOI:
10.1096/fj.201802182R

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