bims-cytox1 Biomed news on
Cytochrome oxidase subunit 1
Issue of 2017‒05‒12
two papers selected by
Gavin McStay
New York Institute of Technology


  1. Mitochondrion. 2017 May 03. doi: 10.1016/j.mito.2017.04.005
    Abstract:  The NADH:ubiquinone oxidoreductase (complex I) is the largest member of the mitochondrial respiratory chain. Its FMN cofactor accepts two electrons from NADH and transfers them to ubiquinone via a chain of iron-sulphur centers. A central core of 14 highly conserved subunits can couple electron transfer to proton translocation. The mammalian enzyme has an additional ~30 accessory subunits. Complex I has important bioenergetic and metabolic functions and is a known source of reactive oxygen species; these functions link it to a number of hereditary and degenerative diseases. For many complex I deficiencies, the primary defect is not in a subunit-encoding gene, but rather in an assembly factor or chaperone that participates in the biogenesis of newly synthesized complex I from individual subunits and cofactors. NDUFAF6 encodes a complex I assembly factor and mutations result in complex I deficiency, Leigh syndrome or Acadian variant Fanconi syndrome. Human NDUFAF6 is a mitochondria-targeted 333-amino acid protein belonging to the family of squalene and phytoene synthases. Sequence and structural information suggests that NDUFAF6 likely has enzymatic activity, but one that has evolved considerable differences from canonical squalene and phytoene synthases. Most but not all metazoans have an NDUFAF6 ortholog, indicating that in some organisms, complex I biogenesis does not require this protein. NDUFAF6 is a peripheral membrane protein and predictions identify a conserved C-terminal attachment site that have implications for substrate access.
    Keywords:  Assembly factor; Mitochondrial disease; Monotopic protein; NADH ubiquinone oxidoreductase; Phylogeny; Structural model
  2. J Biol Chem. 2017 May 05. doi: 10.1074/jbc.M117.783357
    Abstract:  The human aminopeptidase XPNPEP3 is associated with cystic-kidney disease and TNF-TNFR2 cellular signaling. Its yeast and plant homolog Icp55 processes several imported mitochondrial matrix proteins leading to their stabilization. However, the molecular basis for the diverse roles of these enzymes in the cell is unknown. Here, we report the crystal structure of human XPNPEP3 with bound apstatin product at 1.65 Å resolution and compare its in-vitro substrate specificity with those of fungal Icp55 enzymes. In contrast to the suggestions by earlier in-vivo studies of mitochondrial processing, we found that these enzymes are genuine Xaa-Pro aminopeptidases, which hydrolyze peptides with proline at the second position (P1'). The mitochondrial processing activity involving cleavage of peptides lacking P1' proline was also detected in the purified enzymes. A wide proline pocket as well as molecular complementarity and capping at the S1 substrate site of XPNPEP3 provide the necessary structural features for processing the mitochondrial substrates. However, this activity was found to be significantly lower as compared to Xaa-Pro aminopeptidase activity. Due to similar activity profiles of Icp55 and XPNPEP3 we propose that XPNPEP3 plays the same mitochondrial role in humans as Icp55 does in yeast. Both Xaa-Pro aminopeptidase and mitochondrial processing activities of XPNPEP3 have implications towards mitochondrial fitness and cystic-kidney disease. Furthermore, the presence of both these activities in Icp55 elucidates the unexplained processing of the mitochondrial cysteine desulfurase Nfs1 in yeast. The enzymatic and structural analyses reported here provide a valuable molecular framework for understanding the diverse cellular roles of XPNPEP3.
    Keywords:  X-ray crystallography; aminopeptidase; enzyme structure; metalloenzyme; tumor necrosis factor (TNF)