Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Understanding the molecular recognition of Bacteroides fragilis glycosphingolipids by type I Natural Killer T-cell receptor (#230)

Praveena Thirunavukkarasu 1 , Sungwhan F. Oh 2 3 , Hee Bum Song 4 , Ji-Sun Yoo 3 , Da-Jung Jung 3 , Deniz Ertruk- Hasdemir 2 , Yoon Soo Hwang 4 , ChangWon C. Lee 2 , Jérôme Le Nours 1 , Hyunsoo Kim 4 , Jesang Lee 4 , Richard S. Blumberg 5 , Jamie Rossjohn 1 6 7 , Seung Bum Park 4 , Dennis L. Kasper 2
  1. Infection and Immunity program, Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  2. Department of Immunology, Blavatnik Institute of Harvard Medical school, Boston, USA
  3. Center for Experimental Therapeutics and Reperfusion injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, USA
  4. CRI center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, Republic of Korea
  5. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, USA
  6. Institute of Infection and Immunity, Cardiff University, Heath Park, Cardiff, UK
  7. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Australia, Melbourne, Victoria, Australia

The human gut microbiota is composed of more than 50% of Bacteroides species whose membranes are enriched in sphingolipids. In particular, Bacteroides fragilis produced glycosphingolipids termed as α-Galactosylceramide (BfaGCs) have the ability to activate mouse type I Natural Killer T (NKT) cells upon presentation by the antigen-presenting molecule CD1d. While they share key chemical similarities with the type I NKT cell marker antigen, α-Galactosylceramide (KRN7000), they possess distinctive structural features including short, terminal branching with the variations in their hydroxyl group positions. Here, using X-ray crystallography, we have determined two crystal structures of NKT TCR-mouse CD1d-BfaGC lipid ternary complexes revealing a parallel docking mode of the TCR atop the F’-pocket of CD1d in recognizing the presented bacterial sphingolipids. The measured binding affinities between the mouse CD1d presented BfaGCs and NKT TCR were observed to be in the nanomolar range. As translation of results from benchside to bedside with KRN7000 has proven challenging, our study of these physiologically relevant BfaGCs may open new avenues in designing novel immunomodulatory agents to achieve desired immune outcomes in various clinical conditions. Further, this study sheds light on a better understanding of the existing symbiotic relationship between the microbes producing these endogenous lipids and the host.

 

  1. Sungwhan F. Oh*, Praveena T*, Hee Bum Song, Ji-Sun Yoo, Da-Jung Jung, Deniz Erturk-Hasdemir, Yoon Soo Hwang, Changwon C. Lee, Jérôme Le Nours, Hyunsoo Kim, Jesang Lee, Richard S. Blumberg, Jamie Rossjohn, Seung Bum Park, and Dennis L. Kasper (Nature. 2021 Accepted on 28 September, In Press) (* denotes co-first authors)