... understanding life in molecular detail

Dr Yuan Guo

Multivalent lectin-carbohydrate recognition, signalling and endocytosis, immune regulation, allergy and cancer


Dendritic cell (DC) surface C-type lectins are pattern-recognition-receptors which discriminate self and nonself glycans and instruct immune responses, however, such interactions are also exploited by some pathogens/cancer cells to suppress immunity to develop diseases. I am interested to elucidate how such lectin-glycan recognitions are achieved and how these regulate DC to produce specific immune response signals using protein chemistry, structural molecular biology, nanotechnology and cell biology techniques. I also aim to harness these understandings to treat allergy and cancer.

Current major projects include:
  • Mechanisms of multivalent DC-SIGN/R-glycan recognition
  • DC-SIGN-glycan binding in dendritic cell immune regulation

1: Structural and molecular mechanisms of multivalent C-type lectins, DC-SIGN and DC-SIGNR, glycan recognition.

C-type lectin-glycan interactions mediate cell adhesion, pathogen recognition and immune responses. Multivalency plays a very important role in enhance binding affinity and specificity. In collaboration with Profs. Dejian Zhou and Bruce Turnbull (Astbury Centre for Structural Molecular Biology), we have developed a novel strategy to construct multivalent glycan ligands using strongly fluorescent quantum dots (QDs) as multifunctional scaffolds. We then further developed a multimodal readout strategy combining fluorescence resonance energy transfer (FRET) & TEM imaging. Our results revealed that two closely related tetrameric C-type lectins, dendritic cell receptor DC-SIGN and endothelia cell surface receptor DC-SIGNR place their carbohydrate-binding-domains in different orientation. This explains their different multivalent glycan ligand specificity. By collaborating with Prof. Stefan Pöhlmann (Leibniz Institute for Primate Research, Germany), we showed that the QD-glycans could specifically and potently inhibit DC-SIGN mediated Ebola viral cell entry (J. Am. Chem. Soc. 2017, 139, 11833-11844; Angew. Chem. Int. Ed. 2016, 55, 4738-4742).

We are also collaborating with Prof. Neil Ranson (Astbury Centre for Structural Molecular Biology) to provide the molecular details of DC-SIGN via cryo-EM to elucidate its multivalent glycan recognition mechanism.

2: Mechanisms of DC-SIGN-glycan interaction in dendritic cell signalling and endocytosis function regulation.

DC-SIGN-glycan interactions mediate cytokine production through cross talking with Toll-like receptors. The bound ligands are also internalized for procession and presentation to stimulate T cells. However, the mechanism underlies cytokine production regulation and intracellular routing are unclear. In collaboration with Dr Miriam Wittmann and Prof. Dennis McGonagle (Leeds Institute of Rheumatic and Musculoskeletal Medicine), we are examining how different glycans and multivalent presentations regulate their DC-SIGN binding ability and hence dendritic cell function. This understanding will allow us to target DC-SIGN via specific multivalent glycans to manipulate DC function to treat diseases such as allergy and cancer.

Detailed research programme                  Close ▲
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Lecturer
MRSC

Postdoc (Univeristy of Oxford & Imperial College London) 2003-2007
Senior Research Fellow (University of Leeds) 2007-2008
Wellcome Trust Re-entry Fellow (University of Leeds) 2012-2016
Lecturer (University of Leeds) 2017-present

2.31 Chemistry Building
School of Chemistry
0113 3431420
y.guo@leeds.ac.uk

https://physicalsciences.leeds.ac.uk/staff/394/dr-yuan-guo

Selected Publications

  1. Dissecting multivalent lectin-carbohydrate recognition using polyvalent multifunctional glycan-quantum dots. Guo, Y., Nehlmeier, I., Pool, E., Sakonainsiri, C., Hondow, N., Brown, A., Li, Q., Li, S., Whitworth, J., Li, Z., Yu, A., Brydson, R., Turnbull, W.B., Poehlmann, S. and Zhou, D. (2017) J. Am. Chem. Soc. 139, 11833-11844.

  2. Compact, polyvant mannose-quantum dots as sensitive, ratiometric FRET probes for multivalent protein-ligand interactions. Guo, Y., Sakonainsiri, C., Nehlmeier, I., Fascione, M.A., Zhange, H., Wang, W., Poehlmann, S., Turnbull, W.B. and Zhou, D. (2016) Angew. Chem. Int. Ed. 55, 4738-4742

  3. Structural basis fo distinct ligand-binidng and targeting properties of the receptors DC-SIGN and DC-SIGNR. Feinberg, H., Feinberg, H., Conroy, E., Mitchell, D.A. Alvarez, R., Blixt, O., Taylor, M.E. Weis, W.I. and Drickamer, K. (2004) Nat. Struct. & Mol. Biol. 11, 591-598. 

  4. Extended neck regions stabilized tetramers of the receptors DC-SIGN and DC-SIGNR. Feinberg, H., Feinberg, H., Mitchell, D.A. Drickamer, K. and Weis, W.I. (2005) J. Biol. Chem. 280, 1327-1335.