P48962 · ADT1_MOUSE

  • Protein
    ADP/ATP translocase 1
  • Gene
    Slc25a4
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (PubMed:31341297, PubMed:31618756).
Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity).
In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (PubMed:31341297, PubMed:31489369).
Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis (PubMed:31341297).
Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity) (PubMed:31341297).
Proton transporter activity requires free fatty acids as cofactor, but does not transport it (PubMed:31341297).
Probably mediates mitochondrial uncoupling in tissues that do not express UCP1 (PubMed:31341297).
Also plays a key role in mPTP opening, a non-specific pore that enables free passage of the mitochondrial membranes to solutes of up to 1.5 kDa, and which contributes to cell death (PubMed:31489369).
It is however unclear if SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates it (PubMed:31489369).
Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (PubMed:31618756).

Caution

Was reported as a homodimer (PubMed:11809823).
However, 3D structure data show that it forms a monomer (By similarity).
It is unclear if SLC25A4/ANT1 constitutes a pore-forming component of mitochondrial permeability transition pore (mPTP) (PubMed:14749836, PubMed:31489369).
Initial reports, based on deletion of Slc25a4/Ant1 and Slc25a5/Ant2, suggested that ADP/ATP translocase rather acts as a regulator of mPTP (PubMed:14749836).
However, deletion of all ADP/ATP translocase components (Slc25a4/Ant1, Slc25a5/Ant2 and Slc25a31/Ant4) completely inhibits mPTP, suggesting that ADP/ATP translocase constitutes a pore-forming component of mPTP (PubMed:31489369).
Discrepancy between reports may be caused by overexpression of Slc25a31/Ant4 in mice lacking Slc25a4/Ant1 and Slc25a5/Ant2, which compensates for the loss of Slc25a4/Ant1 and Slc25a5/Ant2 (PubMed:31489369).

Catalytic activity

Activity regulation

The matrix-open state (m-state) is inhibited by the membrane-permeable bongkrekic acid (BKA) (By similarity).
The cytoplasmic-open state (c-state) is inhibited by the membrane-impermeable toxic inhibitor carboxyatractyloside (CATR) (By similarity).
Proton transporter activity is inhibited by ADP:ATP antiporter activity (PubMed:31341297).

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site80ADP (UniProtKB | ChEBI)
Binding site92ADP (UniProtKB | ChEBI)
Binding site235ADP (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentmembrane raft
Cellular Componentmitochondrial inner membrane
Cellular Componentmitochondrial membrane
Cellular Componentmitochondrial outer membrane
Cellular Componentmitochondrial permeability transition pore complex
Cellular Componentmitochondrion
Cellular Componentmyelin sheath
Molecular FunctionATP:ADP antiporter activity
Molecular Functionenzyme binding
Molecular Functionoxidative phosphorylation uncoupler activity
Molecular Functionproton transmembrane transporter activity
Biological Processadaptive thermogenesis
Biological ProcessADP transport
Biological Processapoptotic mitochondrial changes
Biological Processmitochondrial ADP transmembrane transport
Biological Processmitochondrial ATP transmembrane transport
Biological Processnegative regulation of cardiac muscle cell apoptotic process
Biological Processnegative regulation of mitochondrial membrane permeability involved in apoptotic process
Biological Processnegative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
Biological Processnegative regulation of necroptotic process
Biological Processpositive regulation of cell growth involved in cardiac muscle cell development
Biological Processpositive regulation of mitophagy
Biological Processregulation of mitochondrial membrane permeability

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

  • Recommended name
    ADP/ATP translocase 1
  • Alternative names
    • ADP,ATP carrier protein 1
    • ADP,ATP carrier protein, heart/skeletal muscle isoform T1
    • Adenine nucleotide translocator 1
      (ANT 1
      )
    • Solute carrier family 25 member 4

Gene names

    • Name
      Slc25a4
    • Synonyms
      Aac1
      , Anc1, Ant1

Organism names

  • Taxonomic identifier
  • Strains
    • C57BL/6J
    • BALB/cJ
    • OF1
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    P48962
  • Secondary accessions
    • Q62164

Proteomes

Organism-specific databases

Subcellular Location

Mitochondrion inner membrane
; Multi-pass membrane protein
Membrane
; Multi-pass membrane protein
Note: The complex formed with ARL2BP, ARL2 and SLC25A4/ANT1 is expressed in mitochondria (PubMed:11809823).
May localize to non-mitochondrial membranes (By similarity).

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain2-7Mitochondrial intermembrane
Transmembrane8-37Helical; Name=1
Topological domain38-74Mitochondrial matrix
Transmembrane75-99Helical; Name=2
Topological domain100-109Mitochondrial intermembrane
Transmembrane110-130Helical; Name=3
Topological domain131-178Mitochondrial matrix
Transmembrane179-199Helical; Name=4
Topological domain200-210Mitochondrial intermembrane
Transmembrane211-231Helical; Name=5
Topological domain232-273Mitochondrial matrix
Transmembrane274-291Helical; Name=6
Topological domain292-298Mitochondrial intermembrane

Keywords

Phenotypes & Variants

Disruption phenotype

Mice display mitochondrial myopathy affecting heart and skeletal muscles (PubMed:9207786).
Hindlimb muscles exhibit abundant ragged-red fibers, characteristic of mitochondrial myopathies (PubMed:9207786).
Increased mitochondrial activity is observed, reflecting greater mitochondrial content (PubMed:9207786).
In addition, mice are exercise intolerant (PubMed:9207786).
Mice develop chronic progressive external ophthalmoplegia, but show normal ocular motility (PubMed:16303948).
In retina, while abnormalities are observed in extraocular muscles, retinal structure and function are not affected normal (PubMed:20671283).
Cells display impaired mitochondrial uncoupling (PubMed:31341297).
Cells show impaired autophagy, leading to accumulation of aberrant mitochondria (PubMed:31618756).
Mice lacking Slc25a4/Ant1 and Slc25a5/Ant2 in liver still have mitochondrial permeability transition pore (mPTP) activity, although more Ca2+ is required to activate the mPTP (PubMed:14749836).
Deletion of Slc25a4/Ant1, Slc25a5/Ant2 and Slc25a31/Ant4 in liver completely inhibits mPTP (PubMed:31489369).
Mice lacking Slc25a4/Ant1, Slc25a5/Ant2, Slc25a31/Ant4 and Ppif lack Ca2+-induced mPTP formation (PubMed:31489369).

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis43Abolished ADP:ATP antiporter activity without affecting ability to regulate mitophagy; when associated with E-244.
Mutagenesis90Abolished ability to regulate mitophagy.
Mutagenesis123Abolished ability to regulate mitophagy.
Mutagenesis146-147Abolished interaction with TIMM4, thereby abolishing ability to regulate mitophagy.
Mutagenesis244Abolished ADP:ATP antiporter activity without affecting ability to regulate mitophagy; when associated with E-43.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 12 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

PTM/Processing

Features

Showing features for initiator methionine, modified residue, chain.

TypeIDPosition(s)Description
Initiator methionine1Removed
Modified residue2N-acetylglycine
ChainPRO_00000905752-298ADP/ATP translocase 1
Modified residue7Phosphoserine
Modified residue52N6,N6,N6-trimethyllysine
Modified residue147N6-succinyllysine
Modified residue149Phosphoserine
Modified residue150Phosphoserine
Modified residue160S-nitrosocysteine
Modified residue245N6-succinyllysine
Modified residue272N6-succinyllysine

Post-translational modification

Under cell death induction, transglutaminated by TGM2 (PubMed:19644512).
Transglutamination leads to formation of covalent cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming polymers (PubMed:19644512).

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Highly expressed in heart, skeletal muscle and brain.

Gene expression databases

Interaction

Subunit

Monomer (By similarity).
Found in a complex with ARL2, ARL2BP and SLC25A4/ANT1 (PubMed:11809823).
Interacts with ARL2BP (PubMed:11809823).
Interacts with TIMM44; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (PubMed:31618756).

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for repeat, region, motif.

TypeIDPosition(s)Description
Repeat6-98Solcar 1
Repeat111-201Solcar 2
Repeat212-297Solcar 3
Region235-240Important for transport activity
Motif235-240Nucleotide carrier signature motif

Domain

The transmembrane helices are not perpendicular to the plane of the membrane, but cross the membrane at an angle. Odd-numbered transmembrane helices exhibit a sharp kink, due to the presence of a conserved proline residue.

Sequence similarities

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    298
  • Mass (Da)
    32,904
  • Last updated
    2007-01-23 v4
  • Checksum
    3A849FEAB0981462
MGDQALSFLKDFLAGGIAAAVSKTAVAPIERVKLLLQVQHASKQISAEKQYKGIIDCVVRIPKEQGFLSFWRGNLANVIRYFPTQALNFAFKDKYKQIFLGGVDRHKQFWRYFAGNLASGGAAGATSLCFVYPLDFARTRLAADVGKGSSQREFNGLGDCLTKIFKSDGLKGLYQGFSVSVQGIIIYRAAYFGVYDTAKGMLPDPKNVHIIVSWMIAQSVTAVAGLVSYPFDTVRRRMMMQSGRKGADIMYTGTLDCWRKIAKDEGANAFFKGAWSNVLRGMGGAFVLVLYDEIKKYV

Features

Showing features for sequence conflict.

TypeIDPosition(s)Description
Sequence conflict136in Ref. 1; AAC52837

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
U27315
EMBL· GenBank· DDBJ
AAC52837.1
EMBL· GenBank· DDBJ
mRNA
X74510
EMBL· GenBank· DDBJ
CAA52616.1
EMBL· GenBank· DDBJ
mRNA
AF240002
EMBL· GenBank· DDBJ
AAF64470.1
EMBL· GenBank· DDBJ
Genomic DNA
BC003791
EMBL· GenBank· DDBJ
AAH03791.1
EMBL· GenBank· DDBJ
mRNA
BC026925
EMBL· GenBank· DDBJ
AAH26925.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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