VDAC1 Membrane Protein Introduction

Introduction of VDAC1

The voltage-dependent anion channel 1 is an outer mitochondrial membrane (OMM) protein that is encoded by VDAC1 gene. The structure of VDAC1 is characterized by 19 α-strands connected by flexible loops to form a β-barrel, along with a 25-residue-long N-terminal region. Unlike other known transmembrane β-barrels, VDAC1 includes odd number of strands, and the barrel closure is achieved by parallel hydrogen bonding between strands 1 and 19, creating a weak point in the barrel structure. Additionally, the N-terminal helix is required to preserve a cylindrical barrel structure in hVDAC1. VDAC1, thought to be located exclusively in the OMM, has also been localized to cell compartments. These alternate compartments include the plasma membrane of various cells, the sarcoplasmic reticulum of skeletal muscles, the endoplasmic reticulum (ER) of rat cerebellum, and caveolae and caveolae-like domains.

Function of VDAC1 Membrane Protein

VDAC1 forms a channel through the mitochondrial outer membrane and also the plasma membrane. The channel at the outer mitochondrial membrane allows diffusion of small hydrophilic molecules; in the plasma membrane, it is involved in cell volume regulation and apoptosis. VDAC1 exhibits a conductance at voltages between -10 mV and +10 mV across the lipid bilayer. At low voltages (~10 mV), VDAC1 exists in a highly conductive state, with the channel being stable in a long-lived open state. At high positive or negative potentials (>40mV), VDAC1 switches to lower conductance states and presents multiple sub-states with different ionic selectivities and permeabilities. VDAC channels display ion-selectivity that depends on the voltage across the membrane. The open state has a weak anion selectivity whereas the closed state is cation-selective. The role of VDAC1 in cellular metabolism is crucial, where it serves as the main interface between mitochondrial and cellular metabolisms. The functions of VDAC1 in metabolism and energy homeostasis are reflected by its facilitation of the transport of ions, nucleotides and other metabolites up to 5 kDa across the OMM. The cellular expression level of VDAC1 is a crucial factor in the process of mitochondria-mediated apoptosis. Interfering with VDAC1 oligomerization provides the means to overcome tumor chemoresistance and to lay down the foundations for more effective chemotherapy without or with fewer side effects.

Fig.1 VDAC1 monomeric and dimeric structures. Ribbon representation of VDAC1 (PDB ID: 3EMN). Panels (A) and (B) show VDAC1 monomer, while panels (C) and (D) represent VDAC1 dimers. (Shoshan-Barmatz, 2013)

Application of VDAC1 Membrane Protein in Literature

1. Head S.A., et al. Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci U S A. 2015, 112(52): E7276-85. PubMed ID: 26655341
   
   

   This article finds that VDAC1 acts as a direct target of itraconazole and the AMPK-signaling pathway act as a key mediator of its inhibition of mTOR and endothelial cell proliferation.

2. Brahimi-Horn M.C., et al. Knockout of Vdac1 activates hypoxia-inducible factor through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation. Cancer & Metabolism. 2015, 3: 8. PubMed ID: 26322231
   
   

   This article suggests that VDAC1 is not just a pore that allows passage of metabolites; it is a major mitochondrial protein that controls crucial processes involved in vital functions such as metabolism and cell death.

3. Arif T., et al. Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo. Molecular Therapy-Nucleic Acids. 2014, 3: e159. PubMed ID: 24781191
   
   

   This article suggests that VDAC1 silencing by RNA interference (RNAi) dramatically inhibits cancer cell growth and tumor development by disabling the abnormal metabolic behavior of cancer cells, potentially paving the way for a more effective pipeline of anticancer drugs.

4. Huang L., et al. A New Fungal Diterpene Induces VDAC1-dependent Apoptosis in Bax/Bak-deficient Cells. Journal of Biological Chemistry. 2015, 290(39): 23563-78. PubMed ID: 26253170
   
   

   This article reveals that cyathin-R is a potent inducer of apoptosis, acting via VDAC1 yet independently of Bax and Bak. Thus, identifying cyathin-R and VDAC1 as its novel target reveals a route to circumvent a common resistance mechanism of tumor cells.

5. Monaco G., et al. The BH4 domain of anti-apoptotic Bcl-XL, but not that of the related Bcl-2, limits the voltage-dependent anion channel 1 (VDAC1)-mediated transfer of pro-apoptotic Ca²⁺ signals to mitochondria. Journal of Biological Chemistry. 2015, 290(14): 9150-61. PubMed ID: 25681439
   
   

   This article suggests that Bcl-XL at the MAMs is able to regulate apoptosis by modulating Ca²⁺ uptake into the mitochondria and rendering cells more resistant to increased Ca²⁺ release from the ER.

VDAC1 Preparation Options

Membrane protein studies have advanced significantly over the past few years. Based on our versatile Magic™ membrane protein production platform, we could offer a series of membrane protein preparation services for worldwide customers in reconstitution forms as well as multiple active formats. Aided by our versatile Magic™ anti-membrane protein antibody discovery platform, we also provide customized anti-VDAC1 antibody development services.

• Magic™ Membrane Protein Production Platform
• Magic™ Anti-Membrane Protein Antibody Discovery Platform

During the past years, Creative Biolabs has successfully generated many functional membrane proteins for our global customers. We are happy to accelerate the development of our clients’ programs with our one-stop, custom-oriented service. For more detailed information, please feel free to contact us.

Reference

1. Shoshan-Barmatz V, et al. (2013). Oligomerization of the mitochondrial protein VDAC1: from structure to function and cancer therapy. Progress in molecular biology and translational science. 117: 303-34.

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