High Resolution Structure and Double Electron-Electron Resonance of the Zebrafish Voltage-dependent Anion Channel 2 Reveal an Oligomeric Population

Schredelseker, Johann; Paz, Adrian; López, Carlos J.; Altenbach, Christian; Leung, Calvin; Drexler, Maria K.; Chen, Jau-Nian; Hubbell, Wayne L.; Abramson, Jeff

doi:10.1074/jbc.m113.497438

Cited by 123 publications

(188 citation statements)

References 45 publications

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“…Fortunately, the zfV2 structure has recently become available (37), and our data showed that zfV2, like mV2, supports the Bak/tBid pathway (Fig. 2).…”

Section: Structural Implications Of the Domains Identified By Mutagensupporting

confidence: 54%

“…The only crystallography study of V2 used zebrafish V2 (zfV2) that had >90% sequence similarity to mammalian V2. This work revealed few differences between V1 and V2, mostly confined to the cytoplasmic loops (37).…”

Section: Significancementioning

confidence: 79%

“…Comparison of amino acid sequences in V1, V2, and VDAC3 revealed similar values for all residues except C, which is exclusively higher in mammalian V2 (11 vs. 2 in V1 and 6 in V3). Localization of the C's in the published biophysical model of VDAC (35)(36)(37)(38) showed that four of the C's (48, 77, 104, and 134; shown by blue arrows in Fig. 2A) in V2 are in the linkers between β-sheets.…”

Section: Genetic Rescue Of V2mentioning

confidence: 99%

“…To examine further the effect of both the N-terminal extension and the high numbers of C's in the V2 sequence on the OMM targeting of Bak, we used zfV2 (37). The zfV2 has 82%/ 92% sequence identity/similarity with mouse V2 (mV2), but it lacks the N-terminal extension and contains only one C at the position of 127.…”

Section: Genetic Rescue Of V2mentioning

confidence: 99%

“…Structural predictions of the VDAC family, primarily VDAC1 (V1) have been done using biochemical methods (33,34) or biophysical methods (i.e., NMR, crystallography) (35)(36)(37)(38)(39). These studies uniformly suggest that VDACs are β-barrel-forming transmembrane channels.…”

mentioning

confidence: 99%

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Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Naghdi

Várnai

Hajnóczky

2015

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-dependent anion channel (VDAC) proteins are major components of the outer mitochondrial membrane. VDAC has three isoforms with >70% sequence similarity and redundant roles in metabolite and ion transport. However, only Vdac2 −/− (V2 −/− ) mice are embryonic lethal, indicating a unique and fundamental function of VDAC2 (V2). Recently, a specific V2 requirement was demonstrated for mitochondrial Bak import and truncated Bid (tBid)-induced apoptosis. To determine the relevant domain(s) of V2 involved, VDAC1 (V1) and V2 chimeric constructs were created and used to rescue V2 −/− fibroblasts. Surprisingly, the commonly cited V2-specific N-terminal extension and cysteines were found to be dispensable for Bak import and high tBid sensitivity. In gain-offunction studies, V2 (123-179) was the minimal sequence sufficient to render V1 competent to support Bak insertion. Furthermore, in loss-of-function experiments, T168 and D170 were identified as critical residues. These motifs are conserved in zebrafish V2 (zfV2) that also rescued V2-deficient fibroblasts. Because high-resolution structures of zfV2 and mammalian V1 have become available, we could superimpose these structures and recognized that the critical V2-specific residues help to create a distinctive open "pocket" on the cytoplasmic surface that could facilitate Bak recruitment.

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“…Fortunately, the zfV2 structure has recently become available (37), and our data showed that zfV2, like mV2, supports the Bak/tBid pathway (Fig. 2).…”

Section: Structural Implications Of the Domains Identified By Mutagensupporting

confidence: 54%

Section: Significancementioning

confidence: 79%

Section: Genetic Rescue Of V2mentioning

confidence: 99%

Section: Genetic Rescue Of V2mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Naghdi

Várnai

Hajnóczky

2015

Proc. Natl. Acad. Sci. U.S.A.

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Recombinant yeast VDAC2: a comparison of electrophysiological features with the native form

et al. 2019

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Voltage‐dependent anion channel isoform 2 of the yeast Saccharomyces cerevisiae ( yVDAC 2) was believed for many years to be devoid of channel activity. Recently, we isolated yVDAC 2 and showed that it exhibits channel‐forming activity in the planar lipid bilayer system when in its so‐called native form. Here, we describe an alternative strategy for yVDAC 2 isolation, through heterologous expression in bacteria and refolding in vitro . Recombinant yVDAC 2, like its native form, is able to form voltage‐dependent channels. However, some differences between native and recombinant yVDAC 2 emerged in terms of voltage dependence and ion selectivity, suggesting that, in this specific case, the recombinant protein might be depleted of post‐translational modification(s) that occur in eukaryotic cells.

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STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

Zhu

Zhou

et al. 2022

Advanced Science

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STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune‐friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity‐independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non‐canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage‐dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75‐mediated MERC (mitochondria‐ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING‐C88/C91 palmitoylation and inhibiting STING palmitoyl‐transferases ZDHHCs by 2‐BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity‐independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.

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High Resolution Structure and Double Electron-Electron Resonance of the Zebrafish Voltage-dependent Anion Channel 2 Reveal an Oligomeric Population

Cited by 123 publications

References 45 publications

Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Recombinant yeast VDAC2: a comparison of electrophysiological features with the native form

STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

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