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Biogenesis and functional mechanism of mitochondrial sulfhydryl oxidase proteins in health and disease

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  • Full or part time
    Dr H Lu
    Prof N Scrutton
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Mitochondrial sulfhydryl oxidases Erv1/ALR play an essential role in biogenesis of mitochondria – the power plant of eukaryotic cells. They are essential components of the mitochondrial import and assembly (MIA) pathways, which catalyse the import and oxidative folding of many mitochondrial proteins. Both Erv1 (in yeast) and ALR (in human) are flavoproteins using FAD as a cofactor for their function. Flavoproteins are an important group of proteins; they have been widely employed in bio-catalytic processes. Moreover, a surprisingly large number of flavoproteins have been reported to be associated with diseases caused by mutations, such as the autosomal recessive myopathy caused by a single mutation in human ALR (R194H). Although structure and functional mechanism of the key components of the MIA import pathway has been well studied in recent years, many questions about the biogenesis and function of the Erv1/ALR enzymes are still remain to be answered. We still lack of knowledge on how Erv1/ALR are imported into mitochondria and how the maturation occurred in mitochondria.

This PhD project will focus on investigating the function, folding and cofactor assembly mechanisms of the wild-type and diseases associated mutant Erv1. A wide range of biochemical and biophysical methods, such as protein purification, enzyme activity assay, mitochondrial import, spectroscopic techniques (UV-vis absorption, circular dichroism, fluorescence), and stopped-flow kinetic analyses will be used to address the biogenesis and functional mechanisms of Erv1/ALR in health and disease. An enthusiastic student with a good background in Biochemistry and relevant subjects is required. The student will get training and have opportunity to learn most of the techniques during this PhD project.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).

Informal enquiries may be made directly to the primary supervisor.

References

Mordas A, Tokatlidis K. The MIA pathway: a key regulator of mitochondrial oxidative protein folding and biogenesis. Acc Chem Res. 48(8):2191-9 (2015) Review.

Ceh-Pavia E, Ang SK, Spiller MP, Lu H. The disease-associated mutation of the mitochondrial sulphydryl oxidase Erv1 impairs cofactor binding during its catalytic reaction. Biochem J. 464(3):449-59 (2014)

Ang SK, Lu H. Deciphering structural and functional roles of individual disulfide bonds of the mitochondrial sulfhydryl oxidase Erv1p. J Biol Chem. 284(42):28754-61 (2009).

Di Fonzo, A. et al. The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. Am J Hum Genet 84, 594-604 (2009).

Fass, D. The Erv family of sulfhydryl oxidases. Biochim Biophys Acta. 1783, 557-566 (2008). (Review)



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