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Title: Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1

Abstract

VDAC1 is a key component of the mitochondrial permeability transition pore. To initiate apoptosis and certain other forms of cell death, mitochondria become permeable such that cytochrome c and other pre-apoptotic molecules resident inside the mitochondria enter the cytosol and activate apoptotic cascades. We have shown recently that VDAC1 interacts directly with never-in-mitosis A related kinase 1 (Nek1), and that Nek1 phosphorylates VDAC1 on Ser193 to prevent excessive cell death after injury. How this phosphorylation regulates the activity of VDAC1, however, has not yet been reported. Here, we use atomic force microscopy (AFM) and cytochrome c conductance studies to examine the configuration of VDAC1 before and after phosphorylation by Nek1. Wild-type VDAC1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by Nek1. A VDAC1-Ser193Ala mutant, which cannot be phosphorylated by Nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux. Conversely, a VDAC1-Ser193Glu mutant, which mimics constitutive phosphorylation by Nek1, remains closed by AFM and prevents cytochrome c leakage in the same liposome assays. Our data provide a mechanism to explain how Nek1 regulates cell death by affecting the opening and closing of VDAC1.

Authors:
 [1]; ;  [2];  [3];  [3]
  1. Department of Medicine, Division of Endocrinology, University of California, Irvine (United States)
  2. Department of Molecular Medicine, Institute of Biotechnology (United States)
  3. Department of Medicine, Division of Nephrology (United States)
Publication Date:
OSTI Identifier:
22202469
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 394; Journal Issue: 3; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIONS; APOPTOSIS; ATOMIC FORCE MICROSCOPY; EDTA; ELECTRIC POTENTIAL; ELECTROPHORESIS; GELS; GLUTATHIONE; INJURIES; LEAD SULFIDES; MITOCHONDRIA; MITOSIS; PHOSPHATES; PHOSPHORYLATION; SODIUM; SULFATES

Citation Formats

Chen, Yumay, Gaczynska, Maria, Osmulski, Pawel, Polci, Rosaria, Riley, Daniel J., and Department of Surgery, Transplant Center, The University of Texas, Health Science Center at San Antonio. Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1. United States: N. p., 2010. Web. doi:10.1016/J.BBRC.2010.03.077.
Chen, Yumay, Gaczynska, Maria, Osmulski, Pawel, Polci, Rosaria, Riley, Daniel J., & Department of Surgery, Transplant Center, The University of Texas, Health Science Center at San Antonio. Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1. United States. https://doi.org/10.1016/J.BBRC.2010.03.077
Chen, Yumay, Gaczynska, Maria, Osmulski, Pawel, Polci, Rosaria, Riley, Daniel J., and Department of Surgery, Transplant Center, The University of Texas, Health Science Center at San Antonio. 2010. "Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1". United States. https://doi.org/10.1016/J.BBRC.2010.03.077.
@article{osti_22202469,
title = {Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1},
author = {Chen, Yumay and Gaczynska, Maria and Osmulski, Pawel and Polci, Rosaria and Riley, Daniel J. and Department of Surgery, Transplant Center, The University of Texas, Health Science Center at San Antonio},
abstractNote = {VDAC1 is a key component of the mitochondrial permeability transition pore. To initiate apoptosis and certain other forms of cell death, mitochondria become permeable such that cytochrome c and other pre-apoptotic molecules resident inside the mitochondria enter the cytosol and activate apoptotic cascades. We have shown recently that VDAC1 interacts directly with never-in-mitosis A related kinase 1 (Nek1), and that Nek1 phosphorylates VDAC1 on Ser193 to prevent excessive cell death after injury. How this phosphorylation regulates the activity of VDAC1, however, has not yet been reported. Here, we use atomic force microscopy (AFM) and cytochrome c conductance studies to examine the configuration of VDAC1 before and after phosphorylation by Nek1. Wild-type VDAC1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by Nek1. A VDAC1-Ser193Ala mutant, which cannot be phosphorylated by Nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux. Conversely, a VDAC1-Ser193Glu mutant, which mimics constitutive phosphorylation by Nek1, remains closed by AFM and prevents cytochrome c leakage in the same liposome assays. Our data provide a mechanism to explain how Nek1 regulates cell death by affecting the opening and closing of VDAC1.},
doi = {10.1016/J.BBRC.2010.03.077},
url = {https://www.osti.gov/biblio/22202469}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 394,
place = {United States},
year = {Fri Apr 09 00:00:00 EDT 2010},
month = {Fri Apr 09 00:00:00 EDT 2010}
}