Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane

Abstract How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the me...

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Autores principales:	Mingzhen Zhang, Jie Zheng, Ruth Nussinov, Buyong Ma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a45c17cce0834f309659cdde7e8de2a4
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spelling	oai:doaj.org-article:a45c17cce0834f309659cdde7e8de2a42021-12-02T11:52:19ZRelease of Cytochrome C from Bax Pores at the Mitochondrial Membrane10.1038/s41598-017-02825-72045-2322https://doaj.org/article/a45c17cce0834f309659cdde7e8de2a42017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02825-7https://doaj.org/toc/2045-2322Abstract How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the membranes using computational approaches. Here, we investigate the mechanism at the microsecond time- and nanometer space- scale using MD simulations. Our free energy landscape depicts a low barrier for the permeation of cytochrome C into the Bax C-terminal mouth, with the pathway proceeding to the inner cavity and exiting via the N-terminal mouth. Release is guided by organized charged/hydrophilic surfaces. The hydrophilicity and negative charge of the pore surface gradually increase along the release pathway from the pore entry to the exit opening. Rather than inert passing of the cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. Once the Bax pore is formed in the membrane, with a low energy barrier, the release of cytochrome C may be readily achieved through energy fluctuations. Collectively, our work provides mechanistic insight in atomic detail into the release of cytochrome C through Bax oligomeric pores.Mingzhen ZhangJie ZhengRuth NussinovBuyong MaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mingzhen Zhang Jie Zheng Ruth Nussinov Buyong Ma Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
description	Abstract How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the membranes using computational approaches. Here, we investigate the mechanism at the microsecond time- and nanometer space- scale using MD simulations. Our free energy landscape depicts a low barrier for the permeation of cytochrome C into the Bax C-terminal mouth, with the pathway proceeding to the inner cavity and exiting via the N-terminal mouth. Release is guided by organized charged/hydrophilic surfaces. The hydrophilicity and negative charge of the pore surface gradually increase along the release pathway from the pore entry to the exit opening. Rather than inert passing of the cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. Once the Bax pore is formed in the membrane, with a low energy barrier, the release of cytochrome C may be readily achieved through energy fluctuations. Collectively, our work provides mechanistic insight in atomic detail into the release of cytochrome C through Bax oligomeric pores.
format	article
author	Mingzhen Zhang Jie Zheng Ruth Nussinov Buyong Ma
author_facet	Mingzhen Zhang Jie Zheng Ruth Nussinov Buyong Ma
author_sort	Mingzhen Zhang
title	Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
title_short	Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
title_full	Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
title_fullStr	Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
title_full_unstemmed	Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane
title_sort	release of cytochrome c from bax pores at the mitochondrial membrane
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a45c17cce0834f309659cdde7e8de2a4
work_keys_str_mv	AT mingzhenzhang releaseofcytochromecfrombaxporesatthemitochondrialmembrane AT jiezheng releaseofcytochromecfrombaxporesatthemitochondrialmembrane AT ruthnussinov releaseofcytochromecfrombaxporesatthemitochondrialmembrane AT buyongma releaseofcytochromecfrombaxporesatthemitochondrialmembrane
_version_	1718395121858248704

Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane

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