Yeast ADP/ATP Carrier Isoform 2

Clémençon, Benjamin; Rey, Martial; Trezeguet, Véronique; Forest, Éric; Pélosi, Ludovic

doi:10.1074/jbc.m111.277376

Cited by 17 publications

(6 citation statements)

References 36 publications

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“…The TP4 peptide structure and predicted ANT2 model were uploaded to the GRAMM-X docking server, which was used to perform a rigid body procedure. In the interface residue constraints fields, we restricted the receptor binding sites to the RRRMMM signature sequence from Arg235 to Met240, which is located at the bottom of the cavity and is expected to be involved in ADP/ATP binding [ 44 ]. All ADP/ATP carriers exhibit the RRRMMM consensus sequence, and this motif is highly conserved in ANTs across species [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

Antimicrobial Peptide TP4 Targets Mitochondrial Adenine Nucleotide Translocator 2

Liu

Ting

et al. 2020

Marine Drugs

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Tilapia piscidin (TP) 4 is an antimicrobial peptide derived from Nile tilapia (Oreochromis niloticus), which shows broad-spectrum antibacterial activity and excellent cancer-killing ability in vitro and in vivo. Like many other antimicrobial peptides, TP4 treatment causes mitochondrial toxicity in cancer cells. However, the molecular mechanisms underlying TP4 targeting of mitochondria remain unclear. In this study, we used a pull-down assay on A549 cell lysates combined with LC-MS/MS to discover that TP4 targets adenine nucleotide translocator (ANT) 2, a protein essential for adenine nucleotide exchange across the inner membrane. We further showed that TP4 accumulates in mitochondria and colocalizes with ANT2. Moreover, molecular docking studies showed that the interaction requires Phe1, Ile2, His3, His4, Ser11, Lys14, His17, Arg21, Arg24 and Arg25 residues in TP4 and key residues within the cavity of ANT2. These findings suggest a mechanism by which TP4 may induce mitochondrial dysfunction to disrupt cellular energy metabolism.

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Section: Resultsmentioning

confidence: 99%

Antimicrobial Peptide TP4 Targets Mitochondrial Adenine Nucleotide Translocator 2

Liu

Ting

et al. 2020

Marine Drugs

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“…Given the evidence that ANT1 is a central point of control for oxidative metabolism and that mutations in ANT1 in yeast 31 and humans 32 can cause profound dysfunction, we focused on characterizing the biophysical mechanisms by which ANT1 function might be altered by acetylation of these charged residues. Acetylation of critical positively charged residues of ANT1 could affect the electrostatic properties and inhibit the initial capture or binding of ADP or could perturb its structure or dynamics, possibly changing the shape of its binding pocket or altering molecular dynamics that facilitate ligand recognition or channel opening.…”

Section: Discussionmentioning

confidence: 99%

“…Of the six arginines identified, three are part of the RRRMMM motif, characteristic of all ADP/ATP transporters. 31 Another two mutant arginines in yeast correspond to Arg80 and Arg280 in the human transporter, which bind ADP and flank Lys23 in the bovine crystal structure. Finally, the single most critical lysine in yeast, Lys38, is in a region with a sequence almost identical to that of the regions surrounding Lys23 in human ANT1.…”

Section: Discussionmentioning

confidence: 99%

Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

et al. 2014

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Proteomics techniques have revealed that lysine acetylation is abundant in mitochondrial proteins. This study was undertaken (1) to determine the relationship between mitochondrial protein acetylation and insulin sensitivity in human skeletal muscle, identifying key acetylated proteins, and (2) to use molecular modeling techniques to understand the functional consequences of acetylation of adenine nucleotide translocase 1 (ANT1), which we found to be abundantly acetylated. Eight lean and eight obese nondiabetic subjects had euglycemic clamps and muscle biopsies for isolation of mitochondrial proteins and proteomics analysis. A number of acetylated mitochondrial proteins were identified in muscle biopsies. Overall, acetylation of mitochondrial proteins was correlated with insulin action (r = 0.60; P < 0.05). Of the acetylated proteins, ANT1, which catalyzes ADP–ATP exchange across the inner mitochondrial membrane, was acetylated at lysines 10, 23, and 92. The extent of acetylation of lysine 23 decreased following exercise, depending on insulin sensitivity. Molecular dynamics modeling and ensemble docking simulations predicted the ADP binding site of ANT1 to be a pocket of positively charged residues, including lysine 23. Calculated ADP–ANT1 binding affinities were physiologically relevant and predicted substantial reductions in affinity upon acetylation of lysine 23. Insertion of these derived binding affinities as parameters into a complete mathematical description of ANT1 kinetics predicted marked reductions in adenine nucleotide flux resulting from acetylation of lysine 23. Therefore, acetylation of ANT1 could have dramatic physiological effects on ADP–ATP exchange. Dysregulation of acetylation of mitochondrial proteins such as ANT1 therefore could be related to changes in mitochondrial function that are associated with insulin resistance.

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“…Recent study of yeast Aac2 using hydrogen/deuterium exchange-mass spectrometry showed that the BA-bound Aac2 is structurally different from the CATR-bound form. The BA conformation has better solvent accessibility from the matrix side [26, 27]. Ant has the RRRMMM signature sequence, which is absent from other mitochondrial carriers.…”

Section: Physiological Roles Of Adenine Nucleotide Translocasementioning

confidence: 99%

“…This motif spans over the thinnest part of the channel and the arginine residues are essential for attracting the negatively charged nucleotides to facilitate transport [25, 28, 29]. In addition to the arginine residues, the methionine triplet also contributes to nucleotide translocation or binding [27]. …”

Section: Physiological Roles Of Adenine Nucleotide Translocasementioning

confidence: 99%

Adenine Nucleotide Translocase, Mitochondrial Stress, and Degenerative Cell Death

Liu

Chen

2013

Oxidative Medicine and Cellular Longevity

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Mitochondria are intracellular organelles involved in ATP synthesis, apoptosis, calcium signaling, metabolism, and the synthesis of critical metabolic cofactors. Mitochondrial dysfunction is associated with age-related degenerative diseases. How mitochondrial dysfunction causes cell degeneration is not well understood. Recent studies have shown that mutations in the adenine nucleotide translocase (Ant) cause aging-dependent degenerative cell death (DCD) in yeast, which is sequentially manifested by inner membrane stress, mitochondrial DNA (mtDNA) loss, and progressive loss of cell viability. Ant is an abundant protein primarily involved in ADP/ATP exchange across the mitochondrial inner membrane. It also mediates basal proton leak and regulates the mitochondrial permeability transition pore. Missense mutations in the human Ant1 cause several degenerative diseases which are commonly manifested by fractional mtDNA deletions. Multiple models have been proposed to explain the Ant1-induced pathogenesis. Studies from yeast have suggested that in addition to altered nucleotide transport properties, the mutant proteins cause a global stress on the inner membrane. The mutant proteins likely interfere with general mitochondrial biogenesis in a dominant-negative manner, which secondarily destabilizes mtDNA. More recent work revealed that the Ant-induced DCD is suppressed by reduced cytosolic protein synthesis. This finding suggests a proteostatic crosstalk between mitochondria and the cytosol, which may play an important role for cell survival during aging.

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Yeast ADP/ATP Carrier Isoform 2

Cited by 17 publications

References 36 publications

Antimicrobial Peptide TP4 Targets Mitochondrial Adenine Nucleotide Translocator 2

Antimicrobial Peptide TP4 Targets Mitochondrial Adenine Nucleotide Translocator 2

Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

Adenine Nucleotide Translocase, Mitochondrial Stress, and Degenerative Cell Death

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