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Personal profile

Overview

My research interests can be divided into three themes: 

1. Mitochondrial protein function

2. Protein folding

3. Bio-application of graphene-related materials. 

Research interests

1. Functions and mechanisms of mitochondrial proteins

Mitochondria are critically important organelles of eukaryotic cells, which regulates a wide range of cellular functions, from cell survival and growth to cell death. Mitochondrial dysfunction leads to life threatening diseases, such as cancer, diabetes, stroke, and various neurodegenerative diseases. Therefore, mitochondrial protein homeostasis, biogenesis and function are highly regulated, and the mitochondrial proteome undergoes constant resculpting in response to the changing demands of the cells. To this end, we are studying: (a) the function mitochondrial AAA (ATPase Associated with a variety of Activities) proteases; and (b) the mechanism of the mitochondrial import and assemble (MIA) pathway.

  1. There are two AAA proteases in the mitochondrial IM: i-AAA and m-AAA, which have catalytic domains located in the mitochondrial IMS (i-AAA) and matrix (m-AAA), respectively. They are multifunctional proteins. Using yeast as a model, we showed that i-AAA protease Yme1 can degrade unassembled Tim10 but not that assembled in a complex with Tim9 (Spiller et al, 2015). Now, we are interested in dissecting the roles of the AAA proteases in maintaining mitochondrial function and protein homeostasis, using biochemical assays combined with bioinformatics (e.g. mass spectrometry based quantitative proteomics) analysis. It is critically important for understanding mitochondrial quality control and mitochondrial dysfunction-related diseases.
  2. Protein import and folding is essential for the biogenesis of mitochondria since about 99% of mitochondrial proteins are synthesized in the cytosol and imported into mitochondria for their function. The mitochondrial import and assemble (MIA) pathway is a redox-regulated pathway used for the import of many Cys-containing proteins. It couples protein import and oxidative protein folding together. The key components of MIA pathway included: a sulfhydryl oxidoreductase Mia40, disulphide bond generator Erv1 (called ALR in human), and cytochrome c of the respiration chain. Whilst the interactions between Mia40 and Erv1/ALR have been well studied, a little is known about how Erv1/ALR interacts with cytochrome c and the reaction is regulated. We are interested in understanding the molecular mechanism of Erv1/ALR-cytochrome c interaction, using both computer modeling and experimental approaches.

Further Reading for project a

Opalińska, M.; Jańska, H. AAA Proteases: Guardians of Mitochondrial Function and Homeostasis. Cells 2018, 7, 163.

Spiller et al. Mitochondrial Tim9 protects Tim10 from degradation by the protease Yme1. Biosci Rep. (2015) 35: pii: e00193.

Stefely JA, et al. Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling. Nat Biotechnol. (2016) 34(11):1191-1197.

Further Reading for project b:

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

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

Tang X, Ang SK, Ceh-Pavia E, Heyes DJ, Lu H. Kinetic characterisation of Erv1, a key component for protein import and folding in yeast mitochondria. FEBS J. (2020) 287:1220-1231.

 

2. Oxidative folding of industrially and pharmaceutically important recombinant proteins

Disulphide bond formation is one of the most common post-translational modifications found in proteins. Oxidative protein folding (protein folding and disulphide bond formation) is important for the function and stability of many proteins. In vivo, disulphide bond formation is catalysed by dedicated oxidoreductase systems in specialized compartments. Thus, oxidative protein folding is challenging and often a key problem of recombinant protein production in vitro.  In collaboration with Dr Anil Day, we are interested in studying oxidative protein folding of industrially and pharmaceutically important recombinant proteins, for example, TGF-βs (Transforming Growth Factor beta). TGF-βs are multifunctional cytokines, belonging to the transforming growth factor superfamily, plays an important regulatory role in the differentiation of tissues and cells, and can stimulate or inhibit the proliferation of various cells. Structurally, TGF-βs are dimers linked via an intermolecular disulphide bond with each monomer folded in a cysteine knot conformation stabilised by three intramolecular disulphide bonds. Thus, it is no surprise that recombinant production of TGF-β native proteins is difficult and limited by protein misfolding. We are interested in expressing and purifying these proteins from E. coli., and understanding the folding mechanisms of the target proteins.

Further Reading:

Quaas, B et al. Properties of dimeric, disulfide-linked rhBMP-2 recovered from E. coli derived inclusion bodies by mild extraction or chaotropic solubilization and subsequent refolding. Process Biochemistry (2018) 67, 80-87.

Saaranen, M.J.; Ruddock, L.W. Applications of catalyzed cytoplasmic disulfide bond formation. Biochem. Soc. Trans. (2019), 47, 1223–1231.

Waite, K., Eng, C. From developmental disorder to heritable cancer: it's all in the BMP/TGF-β family. Nat Rev Genet (2003) 4, 763–773.

Zhou M et al, Pilot-scale expression, purification, and bioactivity of recombinant human TGF-β 3 from Escherichia coli. Eur J Pharm Sci (2019);127: 225-232.

3. Bio-applications of graphene-related materials

Graphene and graphene-related materials have attracted huge attention in recent years due to their unique and outstanding properties and a wide range of potential applications. Graphene oxide (GO) has great potential in biomedicine such as drug delivery, tissue engineering, imaging and biosensors because of its biocompatibility and the presence of various functional groups, allowing GO to be further functionalised, conjugated or immobilised with other molecules or nanoparticles. On the other hand, GO is an effective bactericidal agent against different superbugs, and has antiviral activity. In collaboration with Prof Ping Xiao, School of Material Science, we have recently developed a new method to synthesize different-sized GOs at better quality than that of commonly used methods (Sim, Xiao, and Lu, 2021 Carbon). Now, we are interested in investigating how different-sized GOs affect the performance of GO-biomaterials composites, interact with different cells and biomolecules, and to understand the mechanisms by which GOs kill and/or inactivate bacteria and viruses. We would like to explore potential applications of GOs in biomaterials for tissue engineering, antibacterial and antiviral purposes.

Further Reading:

Aunkor MTH, Raihan T,Prodhan SH, Metselaar HSC, Malik SUF, Azad AK. Antibacterial activity of graphene oxidenanosheet against multidrug resistant superbugsisolated from infected patients.R.  Soc.  Open  Sci. (2020) 7: 200640.

Seifi T, Kamali AR. Antiviral performance of graphene-based materials with emphasis on COVID-19: A review. Medicine in Drug Discovery, (2021) 11 Article 100099

Sim HJ, Xiao P, Lu H. Pyrenebutyric acid-assisted room-temperature synthesis of large-size monolayer graphene oxide with high mechanical strength. Carbon (2021) Volume 185: Pages 224-233.

Singh DP, Herrera CE, Singh B, Singh S, Singh RK, Kumar R. Graphene oxide: An efficient material and recent approach for biotechnological and biomedical applications. Mater Sci Eng C Mater Biol Appl. (2018) 86: 173-197. Review

 

Master, MPhil, and PhD projects are available for motivated, self-funded students. Students with a minimum of upper second class honor’s degree (or equivalent) in Biochemistry, Biology, Chemistry, Pharmacutical Sciences, or related subjects are welcome to apply.

For information about projects, please contact Dr Hui Lu, Tel: 0161 275 1553; Email: Hui.lu@manchester.ac.uk

https://pure.manchester.ac.uk/admin/workspace.xhtml?uid=5

For information about MPhil/PhD study and application, please visit

https://www.manchester.ac.uk/study/postgraduate-research/programmes/list/10914/phd-mphil-biochemistry/

 

Qualifications

BSc, MSc, PhD

Biography

1997: D.Phil,Oxford Centre for Molecular Sciences, Oxford University

1997 -2000: Postdoctoral Researcher, Biochemistry Department, Imperial College, London

2000 -2001:Postdoctoral Researcher, Department of Medicine, University College of London

2001 -2003:Postdoctoral Researcher, Biochemistry Department, Manchester University

2003 - 2011: The Royal Society University Research Fellow, Faculty of Life Sciences, Manchester University

2011 – Lecturer of Biochemistry, Faculty of Life Sciences, Manchester University

Teaching

2nd Year Course: BIOL21111 Proteins

2nd Year Biochemistry RSM

Biochemistry Tutorials (1st and 2nd years)

Final Year Project Students (Lab-based, Bioinformatics)

Master Research Project students (Lab-based, Bioinformatics)

MSci Research Project students

Replacement Students

The academic lead of Biosciences International Summer School (BIO-SISS)

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

Doctor of Science

Keywords

  • Mitochondrial protein biogenesis
  • Protein folding and function
  • Thiol-disulphide redox regulation
  • Mitochondrial protein quality control
  • graphene

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