Dr Paul Gary Young
PhD Molecular Medicine (University of Auckland); MSc Medicine (First Class Honours) (University of Auckland); BSc Biochemistry / Molecular Genetics (Massey University)
Paul is a Research Fellow in Structural Biology at the School of Biological Sciences. His current research involves using Xray-crystallography to solve the structures of various proteins involved in bacterial pathogenesis, which include proteins involved in bacterial pili generation and adhesion.
Research | Current
We have projects focused on cell adhesins from GAS, the structure and function of signal peptidases (essential cell surface enzymes in all bacteria) and superantigen-like proteins from S. aureus (involved in immune evasion).
The surface of S. pyogenes is decorated with numerous virulence factors to aid adhesion and colonization. Prominent amongst GAS virulence factors are pili. Pili (or fimbriae) are proteinaceous filaments that extend from the bacterial surface. They are involved in cell adhesion and biofilm formation. We are interested in the structure of pilins and the mechanism of pilus assembly. The structures of pilins have been instrumental in understanding how they are assembled, why they are incredibly stable and how the adhesion at the tip works. GAS pili are built from multiple copies of a single major or backbone pilin (BP), that forms the shaft, with an adhesive pilin at the tip and typically an anchor pilin at the base, all covalently linked like beads on a string. Furthermore, as pili are highly immunogenic we are currently investigating the use of the pilins as a target for vaccine development.
Intramolecular autocatalytic covalent cross-links
The textbook view of proteins is that their structures are largely maintained by numerous weak, non-covalent interactions. Despite the diversity of functional groups on amino acid side chains, proteins have evolved to minimise chemical reactions between them that could prejudice proper protein folding. Thus, disulfide bonds between pairs of cysteine side chains were thought to be the only common covalent cross-links, and for this reason have been the focus of many protein engineering studies aimed at enhancing protein stability. This understanding has been challenged by our labs discovery of two different type of intramolecular autocatalytic covalent cross-links in elongated bacterial surface adhesion proteins; isopeptide bonds, between lysine and asparagine side chains, and ester bonds, formed between threonine and glutamine side chains. These unusual bonds provide greatly enhanced stability to the proteins, which might otherwise be ripped apart in the harsh environment that bacteria experience. We aim to understand why these unusual bonds form, under what circumstances they form, and how widespread these types of cross-links are. Can we find them outside of the limited number of bacterial species we currently know have them. Moreover, can we find even more bizarre and unusual cross-links in the bacteria that grow at high temperature and pressure such as those that are found near underwater volcanic vents?
Areas of expertise
My research is primarily focused on the structure and function of cell surface proteins and virulence factors from Gram-positive bacteria, including Streptococcus pyogenes (Group A Streptococcus [GAS]) and Staphylococcus aureus.
GAS and S. aureus are highly adapted obligate human pathogens. They are the causative agents of a spectrum of diseases ranging from the common ‘Strep throat’ through to severe invasive diseases such as necrotizing fasciitis, toxic shock syndrome, and the post-streptococcal sequelae of acute rheumatic fever (ARF) and rheumatic heart disease (RHD).
Selected publications and creative works (Research Outputs)
- Raynes, J. M., Frost, H. R. C., Williamson, D. A., Young, P. G., Baker, E. N., Steemson, J. D., ... Atatoa Carr, P. E. (2016). Serological evidence of immune priming by group A streptococci in patients with acute rheumatic fever. Frontiers in Microbiology, 7, 1-6. 10.3389/fmicb.2016.01119
Other University of Auckland co-authors: Edward Baker, Thomas Proft, Nikki Moreland, Rod Dunbar, Jacelyn Loh, Jeremy Raynes, John Steemson
- Ting, Y. T., Harris, P. W., Batot, G., Brimble, M. A., Baker, E. N., & Young, P. G. (2016). Peptide binding to a bacterial signal peptidase visualized by peptide tethering and carrier-driven crystallization. IUCrJ, 3 (Pt 1), 10-19. 10.1107/S2052252515019971
Other University of Auckland co-authors: Margaret Brimble, Paul Harris, Edward Baker
- Baker, E., Squire, C., & Young, P. (2015). Self-generated covalent cross-links in the cell-surface adhesins of Gram-positive bacteria. Biochemical Society Transactions, 43 (5), 787-794. 10.1042/BST20150066
Other University of Auckland co-authors: Edward Baker, Christopher Squire
- Baker, E. N., & Young, P. G. (2015). Convergent weaponry in a biological arms race. eLife, 4.10.7554/eLife.08710
Other University of Auckland co-authors: Edward Baker
- Ting, Y. T., Batot, G., Baker, E. N., & Young, P. G. (2015). Expression, purification and crystallization of a membrane-associated, catalytically active type I signal peptidase from Staphylococcus aureus. Acta Crystallographica Section F:Structural Biology Communications, 71 (Pt 1), 61-65. 10.1107/S2053230X1402603X
Other University of Auckland co-authors: Edward Baker
- Young, P. G., Moreland, N. J., Loh, J. M., Bell, A., Atatoa Carr, P., Proft, T., & Baker, E. N. (2014). Structural conservation, variability, and immunogenicity of the T6 backbone pilin of serotype M6 Streptococcus pyogenes. Infect Immun, 82 (7), 2949-2957. 10.1128/IAI.01706-14
Other University of Auckland co-authors: Nikki Moreland, Edward Baker, Thomas Proft, Jacelyn Loh
- Kwon, H., Squire, C. J., Young, P. G., & Baker, E. N. (2014). Autocatalytically generated Thr-Gln ester bond cross-links stabilize the repetitive Ig-domain shaft of a bacterial cell surface adhesin. Proc Natl Acad Sci U S A, 111 (4), 1367-1372. 10.1073/pnas.1316855111
Other University of Auckland co-authors: Christopher Squire, Edward Baker
- Linke-Winnebeck, C., Paterson, N. G., Young, P. G., Middleditch, M. J., Greenwood, D. R., Witte, G., & Baker, E. N. (2014). Structural model for covalent adhesion of the Streptococcus pyogenes pilus through a thioester bond. J Biol Chem, 289 (1), 177-189. 10.1074/jbc.M113.523761
Other University of Auckland co-authors: Edward Baker, Martin Middleditch