Approaching the structure of human VDAC1, a key molecule in mitochondrial cross-talk

Zeth, Kornelius; Meins, Thomas; Vonrhein, Clemens

doi:10.1007/s10863-008-9144-z

Cited by 18 publications

(10 citation statements)

References 26 publications

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“…In addition, as more membrane bound β-barrel crystal structures are determined, exceptions to the list of 10 explicit rules governing porin structure, as outlined by Schulz [12], are found. For example, in recent structures for mitochondrial protein VDAC, the β-barrel is comprised of 19 β-strands (2JK4) [45], [46], where it was previously considered that β-barrels were comprised solely of an even number of strands. In another recent structure, the barrel is made up of 3 subunits, each making up 4 strands of the 12-stranded barrel [47], illustrating another unique barrel fold.…”

Section: Discussionmentioning

confidence: 99%

A 3-Dimensional Trimeric β-Barrel Model for Chlamydia MOMP Contains Conserved and Novel Elements of Gram-Negative Bacterial Porins

et al. 2013

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Chlamydia trachomatis is the most prevalent cause of bacterial sexually transmitted diseases and the leading cause of preventable blindness worldwide. Global control of Chlamydia will best be achieved with a vaccine, a primary target for which is the major outer membrane protein, MOMP, which comprises ∼60% of the outer membrane protein mass of this bacterium. In the absence of experimental structural information on MOMP, three previously published topology models presumed a16-stranded barrel architecture. Here, we use the latest β-barrel prediction algorithms, previous 2D topology modeling results, and comparative modeling methodology to build a 3D model based on the 16-stranded, trimeric assumption. We find that while a 3D MOMP model captures many structural hallmarks of a trimeric 16-stranded β-barrel porin, and is consistent with most of the experimental evidence for MOMP, MOMP residues 320–334 cannot be modeled as β-strands that span the entire membrane, as is consistently observed in published 16-stranded β-barrel crystal structures. Given the ambiguous results for β-strand delineation found in this study, recent publications of membrane β-barrel structures breaking with the canonical rule for an even number of β-strands, findings of β-barrels with strand-exchanged oligomeric conformations, and alternate folds dependent upon the lifecycle of the bacterium, we suggest that although the MOMP porin structure incorporates canonical 16-stranded conformations, it may have novel oligomeric or dynamic structural changes accounting for the discrepancies observed.

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Section: Discussionmentioning

confidence: 99%

A 3-Dimensional Trimeric β-Barrel Model for Chlamydia MOMP Contains Conserved and Novel Elements of Gram-Negative Bacterial Porins

et al. 2013

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“…As such, the formation of a large channel comprising VDAC1 monomers and serving as the Cyto c release channel has been proposed [5,154,155,193,[223][224][225]. Substantial evidence supports the claim that VDAC1 can exist as higher-order oligomers, namely as monomers, dimers, trimers, tetramers, and hexamers, with the formation of higher ordered VDAC1-containing complexes having been demonstrated [154,155,193,195,[230][231][232][233]. In several studies, it has been reported that both purified soluble and membrane-embedded VDAC1 can assemble into dimers, trimers and tetramers in a dynamic process [234].…”

Section: A Vdac1 Oligomeric Structure As a Cyto C Release Pathwaymentioning

confidence: 98%

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Shoshan‐Barmatz

Ben-Hail

Admoni

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

210

254

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VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites, ions, nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of cancer cells. Indeed, this protein is over-expressed in many cancer types, and silencing of VDAC1 expression induces an inhibition of tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both cancer development and therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA able to impair energy and metabolic homeostasis, leading to arrested cancer cell growth and tumor development, as well VDAC1-based peptides that interact with anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of cancer cell to chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target. This article is part of a Special ...

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“…However, recent studies demonstrated that VDAC1 over-expression is accompanying by its oligomerization (Zalk et al, 2005; Goncalves et al, 2007; Hoogenboom et al, 2007; Malia and Wagner, 2007; Shoshan-Barmatz et al, 2008a,b; Zeth et al, 2008; Keinan et al, 2010). VDAC1 has been shown to form different oligomeric states, namely monomers, dimers, trimers, tetramers, hexamers, and higher-order oligomers (see VDAC1 Oligomerization and Function).…”

Section: Vdac1 Expression Levels In Healthy and Cancer Cellsmentioning

confidence: 99%

VDAC1: from structure to cancer therapy

2012

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Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to cancer. Found at the outer mitochondrial membrane, VDAC1 assumes a crucial position in the cell, controlling the metabolic cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. As a metabolite transporter, VDAC1 contributes to the metabolic phenotype of cancer cells. This is reflected by VDAC1 over-expression in many cancer types, and by inhibition of tumor development upon silencing VDAC1 expression. Along with regulating cellular energy production and metabolism, VDAC1 is also a key protein in mitochondria-mediated apoptosis, participating in the release of apoptotic proteins and interacting with anti-apoptotic proteins. The involvement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space is discussed, as is VDAC1 oligomerization as an important step in apoptosis induction. VDAC also serves as an anchor point for mitochondria-interacting proteins, some of which are also highly expressed in many cancers, such as hexokinase (HK), Bcl2, and Bcl-xL. By binding to VDAC, HK provides both metabolic benefit and apoptosis-suppressive capacity that offers the cell a proliferative advantage and increases its resistance to chemotherapy. VDAC1-based peptides that bind specifically to HK, Bcl2, or Bcl-xL abolished the cell’s abilities to bypass the apoptotic pathway. Moreover, these peptides promote cell death in a panel of genetically characterized cell lines derived from different human cancers. These and other functions point to VDAC1 as a rational target for the development of a new generation of therapeutics.

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Approaching the structure of human VDAC1, a key molecule in mitochondrial cross-talk

Cited by 18 publications

References 26 publications

A 3-Dimensional Trimeric β-Barrel Model for Chlamydia MOMP Contains Conserved and Novel Elements of Gram-Negative Bacterial Porins

A 3-Dimensional Trimeric β-Barrel Model for Chlamydia MOMP Contains Conserved and Novel Elements of Gram-Negative Bacterial Porins

The mitochondrial voltage-dependent anion channel 1 in tumor cells

VDAC1: from structure to cancer therapy

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