Effect of the hinge protein on the heme iron site of cytochrome c1

Kim, Chong H.; Yencha, Andrew J.; Bunker, Grant; Zhang, Guang; Chance, Britton; King, Tsoo E.

doi:10.1021/bi00430a002

Cited by 3 publications

(2 citation statements)

References 11 publications

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“…In yeast, the 17 kDa subunit of complex III is the homolog of Hinge protein and deletion mutants are still capable of growth on a nonfermentable substrate, therefore implying that it is not essential for the assembly and function of complex III (Crivellone et al, 1988;Schoppink et al, 1988). Nonetheless, there is evidence that it may exert a regulatory role of complex III and of its association with cytochrome c (Kim et al, 1989;Schoppink et al, 1989). Liu and Bradner (1993) reported upregulation of hinge transcript in a prostate cancer cell line, but the authors actually based subsequent studies on the sequence of the 1p36 transcribed pseudogene, since the genomic sequence they studied and deposited (gi385936) is identical to AC058783 and not to AL122001.…”

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UQCRH gene encoding mitochondrial Hinge protein is interrupted by a translocation in a soft-tissue sarcoma and epigenetically inactivated in some cancer cell lines

et al. 2003

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We previously reported the identification of a novel zincfinger gene, designated ZSG, fused to Ewing sarcoma gene (EWS) by a submicroscopic paracentric inversion of 22q12 in a small round cell sarcoma presenting a translocation t(1;22)(p34;q12). We report here the molecular cloning and characterization of the breakpoint in 1p34, which encompasses the gene coding for mitochondrial Hinge protein ubiquinol-cytochrome C reductase hinge gene (UQCRH). All the three breakpoints, two on 22q12 and one in 1p34, interrupt different genes: EWS, ZSG and UQCRH. We determined the genomic structure of UQCRH, characterized its splicing variants and identified a transcribed processed pseudogene. The analysis of UQCRH expression in normal tissues and cancer cell lines revealed absent expression of UQCRH in two ovarian and one breast cancer cell lines and reduced expression in a further breast carcinoma cell line. CpG island methylation upstream exon 1 was detected in all the three cell lines with absent expression. Moreover, treatment with demethylating agent 5-azacytidine restored UQCRH expression in OAW42 ovarian cancer cells. These data provide preliminary evidence of the inactivation of UQCRH gene in cancer either by structural rearrangements or epigenetic mechanisms. Oncogene ( Keywords: EWS; sarcoma; ovarian carcinoma; hinge protein; mitochondrial complex III Sarcomas are a heterogeneous group of malignancies of mesenchymal origin that frequently display nonrandom chromosomal translations creating specific fusion genes. The Ewing family of tumors (EFT) comprises small round cell sarcomas showing moderate neural differentiation that were considered in the past as distinct entities: Ewing's sarcoma, primitive neuroectodermal tumors, peripheral neuroepithelioma and Askin tumor. It is now well documented that almost 95% of EFT share the presence of EWS-FLI1 fusion gene, detected cytogenetically as t(11;22)(q24;q12), or of four other alternative Ewing sarcoma gene (EWS) fusions with different partners (namely ERG, ETV1, FEV. E1AF) (Kovar, 1998). Other sarcoma types display specific fusion genes involving EWS and different partners: CHOP (12q13) in myxoid liposarcoma, WT1 (11p13) in intra-abdominal desmoplastic small round cell tumor, CHN/TEC (9q22) in myxoid chondrosarcoma, ATF1 (12q13) in malignant melanoma of soft parts and ZSG/ PATZ (22q12) in a small round cell sarcoma. In all cases, the identification of the translocation by FISH and/or of the fusion transcript by RT-PCR currently offers an invaluable clue for the correct diagnosis. The exact functions of EWS protein, an RNA-binding protein, are still unclear, but it is widely proven by in vitro studies that the EWS-related fusion genes act as dominant oncogenes with aberrant transcription and possibly splicing features (Arvand and Denny, 2001).We previously reported the identification of a novel fusion gene between EWS and the novel putative transcription factor ZSG, generated by an intrachromosomal rearrangement of chromosome 22, an inversion of 22q12, in a small round cel...

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UQCRH gene encoding mitochondrial Hinge protein is interrupted by a translocation in a soft-tissue sarcoma and epigenetically inactivated in some cancer cell lines

et al. 2003

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“…Genetic deletion (192) or removal (108) of this subunit leads to a loss of binding of cytochrome c to CYC1 depending on the ionic strength, and at least in yeast, to a decrease in cytochrome c reductase activity of 50%. Crystal structures show that this subunit does not contribute directly to the cytochrome c binding pocket (116,200), but other studies show a perturbation of the CYC1 heme environment when UQCRH is removed (106), and its abundance of acidic residues has been proposed to direct cytochrome c to its actual binding site (200). Phosphorylation of UQCRH has been detected with PhosTag dye (6), and Ser89, located close to the COOH-terminus, has been identified as a phosphorylation site Sites that are unlikely to have an effect on activity based on their location in available high-resolution structures are shown in white.…”

Section: Complex III Phosphorylationmentioning

confidence: 90%

Cardiac mitochondrial matrix and respiratory complex protein phosphorylation

Covián

Balaban

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Covian R, Balaban RS. Cardiac mitochondrial matrix and respiratory complex protein phosphorylation. Am J Physiol Heart Circ Physiol 303: H940 -H966, 2012. First published August 10, 2012; doi:10.1152/ajpheart.00077.2012.-It has become appreciated over the last several years that protein phosphorylation within the cardiac mitochondrial matrix and respiratory complexes is extensive. Given the importance of oxidative phosphorylation and the balance of energy metabolism in the heart, the potential regulatory effect of these classical signaling events on mitochondrial function is of interest. However, the functional impact of protein phosphorylation and the kinase/phosphatase system responsible for it are relatively unknown. Exceptions include the well-characterized pyruvate dehydrogenase and branched chain ␣-ketoacid dehydrogenase regulatory system. The first task of this review is to update the current status of protein phosphorylation detection primarily in the matrix and evaluate evidence linking these events with enzymatic function or protein processing. To manage the scope of this effort, we have focused on the pathways involved in energy metabolism. The high sensitivity of modern methods of detecting protein phosphorylation and the low specificity of many kinases suggests that detection of protein phosphorylation sites without information on the mole fraction of phosphorylation is difficult to interpret, especially in metabolic enzymes, and is likely irrelevant to function. However, several systems including protein translocation, adenine nucleotide translocase, cytochrome c, and complex IV protein phosphorylation have been well correlated with enzymatic function along with the classical dehydrogenase systems. The second task is to review the current understanding of the kinase/phosphatase system within the matrix. Though it is clear that protein phosphorylation occurs within the matrix, based on 32 P incorporation and quantitative mass spectrometry measures, the kinase/phosphatase system responsible for this process is ill-defined. An argument is presented that remnants of the much more labile bacterial protein phosphoryl transfer system may be present in the matrix and that the evaluation of this possibility will require the application of approaches developed for bacterial cell signaling to the mitochondria.kinase; phosphatase; citric acid cycle; oxidative phosphorylation; protein transport; mitochondria intermembrane space; phosphohistidine; adenine nucleotide translocase; pyruvate dehydrogenase; branched chain ␣-ketoacid dehydrogenase THIS REVIEW ARTICLE is part of a collection on Post-translational Protein Modification in Metabolic Stress. Other articles appearing in this collection, as well as a full archive of all Review collections, can be found online at http://ajpheart. physiology.org/.

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