Mitochondrial carrier

Source: Wikipedia, the free encyclopedia.
TCDB
2.A.29
OPM superfamily21
OPM protein1okc
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB2bmnA:9-104 2c3eA:112-206 1ymjA:112-206 1okcA:112-206 1ym6A:112-206
MC Superfamily
Identifiers
Symbol?
InterProIPR023395

Mitochondrial carriers are proteins from

mitochondria.[1] Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family (TC# 2.A.29) and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family (TC# 1.N.6).[2]

Phylogeny

Members of the MC family (SLC25) (TC# 2.A.29) are found exclusively in eukaryotic organelles although they are nuclearly encoded. Most are found in mitochondria, but some are found in

anaerobic fungi, and in amyloplasts
of plants.

SLC25 is the largest solute transporter family in humans. 53 members have been identified in human genome, 58 in A. thaliana and 35 in S. cerevisiae. The functions of approximately 30% of the human SLC25 proteins are unknown, but most of the yeast homologues have been functionally identified.[3][4] See TCDB for functional assignments

Function

Many MC proteins preferentially catalyze the exchange of one solute for another (

carrier proteins, which are involved in energy transfer, have been found in the inner membranes of mitochondria and other eukaryotic organelles such as the peroxisome and facilitate the transport of inorganic ions, nucleotides, amino acids, keto acids and cofactors across the membrane.[5][6][7][8]
Such proteins include:

Functional aspects of these proteins, including metabolite transport, have been reviewed by Dr. Ferdinando Palmieri and Dr. Ciro Leonardo Pierri (2010).

HHH syndrome, aspartate/glutamate isoform 2 deficiency, Amish microcephaly, and neonatal myoclonic epilepsy. These disorders are characterized by specific metabolic dysfunctions, depending on the physiological role of the affected carrier in intermediary metabolism. Defects of mitochondrial carriers that supply mitochondria with the substrates of oxidative phosphorylation, inorganic phosphate and ADP, are responsible for diseases characterized by defective energy production.[15] Residues involved in substrate binding in the middle of the transporter and gating have been identified and analyzed.[8]

Structure

Permeases of the MC family (the human SLC25 family) possess six

transmembrane α-helices. The proteins are of fairly uniform size of about 300 residues. They arose by tandem intragenic triplication in which a genetic element encoding two spanners gave rise to one encoding six spanners.[17] This event may have occurred less than 2 billion years ago when mitochondria first developed their specialized endosymbiotic functions within eukaryotic cells.[18] Members of the MC family are functional and structural monomers although early reports indicated that they are dimers.[3][4]

Most MC proteins contain a primary structure exhibiting three repeats, each of about 100 amino acid residues in length, and both the N and C termini face the intermembrane space. All carriers contain a common sequence, referred to as the MCF motif, in each repeated region, with some variation in one or two signature sequences.[1]

Amongst the members of the mitochondrial carrier family that have been identified, it is the ADP/ATP carrier (AAC; TC# 2.A.29.1.1) that is responsible for importing ADP into the mitochondria and exporting ATP out of the mitochondria and into the cytosol following synthesis.

transmembrane helices that are tilted with respect to the membrane, 3 of them "kinked" due to the presence of prolyl residues.[1]

Residues that are important for the transport mechanism are likely to be symmetrical, whereas residues involved in substrate binding will be asymmetrical reflecting the asymmetry of the substrates. By scoring the symmetry of residues in the sequence repeats, Robinson et al. (2008) identified the substrate-binding sites and salt bridge networks that are important for transport. The symmetry analyses provides an assessment of the role of residues and provides clues to the chemical identities of substrates of uncharacterized transporters.[21]

There are structures of the mitochondrial ADP/ATP carrier in two different states. One is the cytoplasmic state, inhibited by

bongkrekic acid, in which the substrate binding site is accessible to the mitochondrial matrix, i.e. the fungal mitochondrial ADP/ATP carrier PDB: 6GCI​.[25] In addition, there are structures of the calcium regulatory domains of the mitochondrial ATP-Mg/Pi carrier in the calcium-bound state PDB: 4ZCU​/PDB: 4N5X​ [26][27] and mitochondrial aspartate/glutamate carriers in different regulatory states PDB: 4P5X​/PDB: 4P60​/PDB: 4P5W​.[28]

Substrates

Mitochondrial carriers transport amino acids, keto acids, nucleotides, inorganic ions and co-factors through the mitochondrial inner membrane. The transporters consist of six transmembrane alpha-helices with threefold pseudo-symmetry.[29]

The transported substrates of MC family members may bind to the bottom of the cavity, and translocation results in a transient transition from a 'pit' to a 'channel' conformation.[30] An inhibitor of AAC, carboxyatractyloside, probably binds where ADP binds, in the pit on the outer surface, thus blocking the transport cycle. Another inhibitor, bongkrekic acid, is believed to stabilize a second conformation, with the pit facing the matrix. In this conformation, the inhibitor may bind to the ATP-binding site. Functional and structural roles for residues in the TMSs have been proposed.[31][32] The mitochondrial carrier signature, Px[D/E]xx[K/R], of carriers is probably involved both in the biogenesis and in the transport activity of these proteins.[33] A homologue has been identified in the mimivirus genome and shown to be a transporter for dATP and dTTP.[34]

Examples of transported compounds include:

Examples

Human proteins containing this domain include:

Yeast Ugo1 is an example of the MMF family, but this protein has no human ortholog.

References

  1. ^
    PMID 16756509
    .
  2. PMID 8140286
    .
  3. ^
    PMID 17566106
    .
  4. ^
    PMID 17056710
    .
  5. PMID 2158156
    .
  6. PMID 8487299
    .
  7. PMID 8291088
    .
  8. ^
    S2CID 1837739
    .
  9. ^
    S2CID 21307218
    .
  10. S2CID 35726914
    .
  11. doi:10.1016/0959-440X(92)90081-H
    .
  12. S2CID 25304722
    .
  13. PMID 19745225
    .
  14. PMID 20533899
    .
  15. ^
    PMID 18406340
    .
  16. PMID 23988125
    .
  17. PMID 23266187
    .
  18. PMID 8325039
    .
  19. PMID 27001633
    .
  20. PMID 10400693
    .
  21. PMID 19001266
    .
  22. S2CID 4338748
    .
  23. S2CID 30874107
    .
  24. ^
    PMID 24474793
    .
  25. PMID 30611538
    .
  26. PMID 26164100
    .
  27. PMID 24332718
    .
  28. PMID 25410934
    .
  29. S2CID 20100085
    .
  30. PMID 16759636
    .
  31. PMID 16962611
    .
  32. PMID 17442340
    .
  33. PMID 18032784
    .
  34. PMID 17229695
    .

External links
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