Laboratories

Kevin Waldron, PhD

Laboratory of Metalloprotein Biology

ORCID: 0000-0002-5577-7357

E-mail:

Research Scope

The Laboratory of Metalloprotein Biology studies the structure and function of metalloproteins and metalloenzymes. We aim to understand how microorganisms acquire, handle, use and detoxify essential metal ions. We are particularly interested in how these fundamental homeostatic processes influence virulence and the outcomes of bacterial infection. The long-term goal of our studies is to exploit this knowledge to develop novel targets for future antibacterial drug discovery.

Research

Main Scientific Achievements

  • We uncovered a novel mechanism by which cells regulate metal selectivity, demonstrating that a pair of closely related metalloenzymes from cyanobacteria, with nearly identical metal selectivity, are loaded in vivo with different metals, from opposite ends of the Irving-Williams series.
  • We identified the founding members of a new family of copper storage proteins, the Csps, characterising a novel component of bacterial copper homeostasis with implications for copper handling and utilisation by important environmental bacteria and medically important pathogens.
  • We demonstrated a unique evolutionary adaptation in Staphylococcus aureus that enables this pathogen to survive the manganese starvation that it experiences during infection of the host through its evolution of a ‘cambialistic’ superoxide dismutase enzyme that exhibits cofactor flexibility, catalysing its reaction with either manganese or iron.

Research Description

All life on Earth depends on metals. Although present in trace quantities relative to the six organic elements that constitute biological macromolecules, the essential metals (Mg, Ca, Mn, Fe, Co, Ni, Cu, Zn and Mo) play crucial roles that make them indispensable to biology. They act as charge carriers, as messengers in cell signaling, and hold together the structures of metal-requiring proteins (metalloproteins). Most importantly they directly participate in chemical reactions as essential cofactors for metal-dependent enzymes (metalloenzymes). It’s estimated that approximately one-third of all proteins in nature require metals, with an even higher proportion of enzymes predicted to require metals for catalysis.

My laboratory aims to understand the essential roles of metal ions in the structure and function of individual metalloproteins and metalloenzymes. We combine core methods in biochemistry, structural biology and biophysics to interrogate the mechanisms by which proteins utilise metals to impart structure or to facilitate catalysis, and in turn, how the protein architecture exploits and manipulates the reactivity of the metal ions. We seek to clarify the molecular mechanisms that regulate the metal specificity of metalloenzymes, i.e. their requirement to associate with one specific type of metal ion to perform their catalysis optimally, and the metal selectivity of metalloproteins, i.e. their metal binding preferences.

Furthermore, we study the mechanisms of metal homeostasis, the processes by which cells control metal availability. Due to their essential nature and their inherent potential for toxicity, all living cells possess complex, integrated cellular systems for controlling intracellular metal uptake through regulation of metal import, export, intracellular delivery, storage and sensing. Homeostasis is crucial in ensuring that each metal-requiring protein becomes associated only with its correct, target metal ion in vivo, preventing their inactivation by binding the ‘wrong’ metal ion. Homeostasis also prevents deleterious effects on the cell caused by excess concentrations of metal ions.

Methodology

Our lab uses a multidisciplinary approach to study primarily bacterial systems. Our in vitro studies leverage core methods in biochemistry, combined with structural biology and biophysics, to interrogate the structure and function of individual metalloproteins and metalloenzymes. We combine this with microbiological methods to understand the role of those metalloproteins and metalloenzymes in living cells through genetic manipulation of bacteria for phenotypic analysis, biochemical assay, and multi-omics approaches. To facilitate these studies, we collaborate with numerous world-leading laboratories.

Selected Publications

  • An evolutionary path to altered cofactor specificity in a metalloenzyme. Barwinska-Sendra A, Garcia YM, Sendra KM, Baslé A, Mackenzie ES, Tarrant E, Card P, Bicep C, Un S, Kehl-Fie TE, Waldron KJ. Nature Communications, 11, 2738. 2020. https://doi.org/10.1038/s41467-020-16478-0.
  • A superoxide dismutase capable of using iron or manganese promotes the resistance of Staphylococcus aureus to calprotectin and nutritional immunity. Garcia YM, Barwinska-Sendra A, Tarrant E, Skaar EP, Waldron KJ, Kehl-Fie TE. PLoS Pathogens, 13, e1006125. 2017. https://doi.org/10.1371/journal.ppat.1006125.
  • A four-helix bundle stores copper for methane oxidation. Vita N, Platsaki S, Baslé A, Allen SJ, Paterson NG, Crombie AT, Murrell JC, Waldron KJ & Dennison C. Nature, 525, 140-3. 2015. https://doi.org/10.1038/nature14854.
  • Metalloproteins and metal sensing. Waldron KJ, Rutherford JC, Ford D & Robinson NJ. Nature, 460, 823-830. 2009. https://doi.org/10.1038/nature08300.
  • Protein-folding location can regulate manganese versus copper- or zinc-binding. Tottey S, Waldron KJ, Firbank SJ, Reale B, Bessant C, Sato K, Cheek TR, Gray J, Banfield MJ, Dennison C & Robinson NJ. Nature, 455, 1138-1142. 2008. https://doi.org/10.1038/nature07340.

Collaborations

  • Thomas Kehl-Fie, School of Molecular & Cellular Biology, University of Illinois at Urbana Champaign, USA, https://mcb.illinois.edu/faculty/profile/kehlfie/.
  • Sun Un, Department of Biochemistry, Biophysics and Structural Biology, Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, Gif-sur-Yvette, France, https://frisbi.eu/centers/south-paris/epr/.
  • Julie Morrissey, Department of Genetics and Genome Biology, University of Leicester, Leicester, UK, https://www2.le.ac.uk/departments/genetics/people/morrissey.
  • Xingxiang Chen, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China, https://cvmen.njau.edu.cn/info/1231/1184.htm.
  • Karrera Djoko, Department of Biosciences, Durham University, Durham, UK, https://www.durham.ac.uk/staff/karrera-djoko/.
  • Jon Marles-Wright, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK, http://www.marles-wright-lab.org/.

Prizes and Awards

  • Arturo Leone Young Investigator Award. 2018. 11th International Copper Meeting, Italy.

Publications

Publication not found.

Leader

KEVIN WALDRON, PhD

My love of science and desire to better understand nature arose at a young age, while growing up in the north-east of England and surrounded by the beautiful natural landscapes and coasts of Northumberland. Approaching university, I chose to mix my two favourite sciences, biology and chemistry, studying for a joint-honours course in Biological Chemistry in Sheffield, UK. During this period, I began to develop a love of performing experiments and discovering new knowledge, and got my first taste of real at-the-lab-bench research during undergraduate and Masters research projects. This led me to pursue a PhD to further my research experience, moving to Newcastle University to study in the lab of Prof Nigel Robinson (now at Durham University, UK). This project leveraged both of these interests in chemistry and biology by studying the structure and function of metalloproteins and the biological systems that regulate bacterial metal homeostasis. Since then, I have sought to carve out my own research niche in this exciting field.

  • AUTHOR IDENTIFIERS

ORCID: 0000-0002-5577-7357
RESEARCHER ID: J-2368-2016
Google Scholar: B8xT3UAAAAJ

  • DEGREES

2007 – Ph.D. Faculty of Medical Sciences, Newcastle University, UK, biochemistry
2003 – M.Chem. Department of Chemistry, Sheffield University, UK, (Honors), biological Chemistry

  • PROFESSIONAL EMPLOYMENT/ EXPERIENCE

Since 2022 – Assistant Professor, Institute of Biochemistry and Biophysics, Polish Academy of Sciences
2009 – 2022 – Research Fellow, Faculty of Medical Sciences, Newcastle University, UK
2006 – 2009 – Research Associate, Faculty of Medical Sciences, Newcastle University, UK

  • PROFESSIONAL AFFILIATIONS

2019 – present – Guest Professor, Nanjing Agricultural University, PR China
2018 – present – Expert, Research Grant Board: Biological Sciences, Royal Society, UK
2014 – present – Member, Microbiology Society, UK
2014 – present – Member, Biochemical Society, UK

  • AWARDS AND FELLOWSHIPS

2018 – Arturo Leone Young Investigator Award
2013-2018 – Sir Henry Dale Fellowship, Wellcome Trust, UK
2009-2013 – Faculty Fellowship, Newcastle University, UK

  • DOCTORATES DEFENDED UNDER LAB LEADER’S SUPERVISION

Semeli Platsaki (auxiliary supervision), Jack Stevenson (principal supervision), Eliona Tsefou (auxiliary supervision), Anna Barwinska-Sendra (principal supervision), Gianpiero Landolfi (auxiliary supervision), Yasmin Ahmed (auxiliary supervision), Paola Lanzoni (auxiliary supervision), Safa Alsharif (principal supervision), Andrea Giachino (principal supervision)

Grants

  • The catalysis, metal specificity and evolution of superoxide dismutases. PI: Kevin Waldron. Maestro 13, National Science Centre, Poland. 2022-2026. PLN 4,299,200.
  • Leveraging host-imposed metal starvation to elucidate the molecular and environmental factors that dictate metal utilization by the iron/manganese superoxide dismutase superfamily. (Co-I sub-contract; PI Dr TE Kehl-Fie, Illinois at Urbana-Champaign). R01, National Institutes of Health (NIAID), USA. 2021-2026. $668,130 direct, of $3,034,465 total.