Post-translational modifications of VDAC1 and VDAC2 cysteines from rat liver mitochondria

Saletti, Rosaria; Reina, Simona; Pittalà, Maria Gaetana Giovanna; Magrì, Andrea; Cunsolo, Vincenzo; Foti, Salvatore; Pinto, Vito De

doi:10.1016/j.bbabio.2018.06.007

Cited by 33 publications

(75 citation statements)

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“…In the outer mitochondrial membrane, voltagedependent anion channels (VDACs 1, 2, and 3) transport small metabolites into the mitochondrial intermembrane space. VDAC2 and 3 have a large number of cysteine residues at the pore opening, which regulate pore activity upon oxidation [48][49][50]. In the inner mitochondrial membrane, adenine nucleotide transporters (ANTs) [51], uncoupling proteins (UCPs) [52], and mitochondrial calcium uniporter (MCU) [53] have all been shown to be regulated by cysteine oxidation.…”

Section: Mitochondrial Transporter Oxidation (Regulatory)mentioning

confidence: 99%

Cysteine reactivity across the subcellular universe

Bak

Bechtel

Falco

et al. 2019

Current Opinion in Chemical Biology

104

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Cysteine residues are concentrated at key functional sites within proteins, performing diverse roles in metal binding, catalysis, and redox chemistry. Chemoproteomic platforms to interrogate the reactive cysteinome have developed significantly over the past 10 years, resulting in a greater understanding of cysteine functionality, modification, and druggability. Recently, chemoproteomic methods to examine reactive cysteine residues from specific subcellular organelles have provided significantly improved proteome coverage and highlights the unique functionalities of cysteine residues mediated by cellular localization. Here, the diverse physicochemical properties of the mammalian subcellular organelles are explored in the context of their effects on cysteine reactivity. The unique functions of cysteine residues found in the mitochondria and endoplasmic reticulum are highlighted, together with an overview into chemoproteomic platforms employed to investigate cysteine reactivity in subcellular organelles.

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Section: Mitochondrial Transporter Oxidation (Regulatory)mentioning

confidence: 99%

Cysteine reactivity across the subcellular universe

Bak

Bechtel

Falco

et al. 2019

Current Opinion in Chemical Biology

104

View full text Add to dashboard Cite

show abstract

“…More recently, the amino acid composition of the three mammalian VDAC isoforms was examined, showing interesting peculiarities [ 20 ]. The cysteine content of the three isoforms is different, and this was correlated to their oxidation and potential disulfide bond formation [ 21 ]. The three isoforms carry strikingly different amounts of cysteine whose different role has been hypothesized [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators

Zinghirino

Pappalardo

Messina

et al. 2020

IJMS

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VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs’ presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon–intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.

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“…With increasing incidence of proteotoxic disorders worldwide, a cure for AD, PD, aging, and other forms of neurodegeneration is extremely vital. A suggested cure is to inhibit protein aggregation (Cuadrado-Tejedor et al, 2011; Smilansky et al, 2015; Boulbrima et al, 2016; Magrì et al, 2016; Saletti et al, 2018). Several proteins can form neurodegenerative aggregates (Iadanza et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Helix–strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3

Gupta

Mahalakshmi

2019

Journal of General Physiology

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Voltage-dependent anion channels (VDACs) are β-sheet–rich transmembrane β-barrels that are vital for metabolite transport across the mitochondrial membrane. Under cellular stress, human VDACs hetero-oligomerize and coaggregate with proteins that can form amyloidogenic and neurodegenerative deposits, implicating a role for VDACs in proteotoxicity. However, whether VDACs possess intrinsic interaction sites that can lead to protein aggregation is not known. Here, we couple a systematic thiol replacement strategy with far-UV circular dichroism spectropolarimetry and UV scattering spectroscopy to map aggregation-prone regions of human VDACs, using isoform 3 as our model VDAC. We show that the region comprising strands β7–β9 is highly aggregation prone. Further, we find that an α1–β7–β9 interaction (involving the hVDAC3 N-terminal α1 helix) can lower protein aggregation, whereas perturbations of this interaction promote VDAC aggregation. We also show that hVDAC3 aggregation proceeds via a partially unfolded structure. Our findings allow us to propose a plausible mechanism for the role of human VDACs in forming proteotoxic aggregates in the cell. The key target sites on VDACs—strands β7–β9—may be useful for developing VDAC aggregation inhibitors.

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Post-translational modifications of VDAC1 and VDAC2 cysteines from rat liver mitochondria

Cited by 33 publications

References 50 publications

Cysteine reactivity across the subcellular universe

Cysteine reactivity across the subcellular universe

Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators

Helix–strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3

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