Structure and unusual binding mechanism of the hyaluronan receptor LYVE-1 mediating leucocyte entry to lymphatics
Immune surveillance involves the continual migration of antigen-scavenging immune cells from the tissues to downstream lymph nodes via lymphatic vessels. To enable such passage, cells first dock with the lymphatic entry receptor LYVE-1 on the outer surface of endothelium, using their endogenous hyaluronan glycocalyx, anchored by a second hyaluronan receptor, CD44. Why the process should require two different hyaluronan receptors and by which specific mechanism the LYVE-1•hyaluronan interaction enables lymphatic entry is however unknown. Here we describe the crystal structures and binding mechanics of murine and human LYVE-1•hyaluronan complexes. These reveal a highly unusual, sliding mode of ligand interaction, quite unlike the conventional sticking mode of CD44, in which the receptor grabs free hyaluronan chain-ends and winds them in through conformational re-arrangements in a deep binding cleft, lubricated by a layer of structured waters. Our findings explain the mode of action of a dedicated lymphatic entry receptor and define a distinct, low tack adhesive interaction that enables migrating immune cells to slide through endothelial junctions with minimal resistance, while clinging onto their hyaluronan glycocalyx for essential downstream functions.
Authors
- Robert J.C. Gilbert (ORCID: https://orcid.org/0000-0001-9336-5604)
- Tao Ni (ORCID: https://orcid.org/0000-0001-7268-0306)
- Suneale Banerji (ORCID: https://orcid.org/0000-0002-1179-3152)
- Emanuele Paci
- Fouzia Bano (ORCID: https://orcid.org/0000-0003-0634-7091)
- Ralf P. Richter (ORCID: https://orcid.org/0000-0003-3071-2837)
- Dixy E. Green (ORCID: https://orcid.org/0000-0002-6237-0889)
- Paul L. DeAngelis (ORCID: https://orcid.org/0000-0002-8843-1344)
- Iain W. Manfield (ORCID: https://orcid.org/0000-0003-3765-0325)
- Martin Lepšı́k (ORCID: https://orcid.org/0000-0003-2607-8132)
- David G. Jackson
- Kevin W. Cook
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Leeds (GB)
- Centre for Human Genetics (GB)
- Czech Academy of Sciences (CZ)
- University of Oxford (GB)
- Osservatorio astronomico di Bologna (IT)
- CIC biomaGUNE (ES)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Université Bourgogne Franche-Comté (FR)
- MRC Human Immunology Unit (GB)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- University of Oklahoma Health Sciences Center (US)
- University of Hong Kong (HK)
- Université Grenoble Alpes (FR)
- Umeå University (SE)
- Medical Research Council (GB)
- University of Bologna (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1038/s41467-025-57866-8
- Citations
- 13
- Primary Topic
- Lymphatic System and Diseases
- Type
- article
- Field-Weighted Citation Impact
- 13.59
Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council