Structure and unusual binding mechanism of the hyaluronan receptor LYVE-1 mediating leucocyte entry to lymphatics

Fouzia Bano, Suneale Banerji, Tao Ni, Dixy E. Green, Kalila R. Cook, Iain W. Manfield, Paul L. DeAngelis, Emanuele Paci, Martin Lepšík (), Robert J. C. Gilbert (), Ralf P. Richter () and David G. Jackson ()
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Fouzia Bano: University of Leeds
Suneale Banerji: University of Oxford
Tao Ni: University of Oxford
Dixy E. Green: University of Oklahoma Health Sciences Center
Kalila R. Cook: University of Leeds
Iain W. Manfield: University of Leeds
Paul L. DeAngelis: University of Oklahoma Health Sciences Center
Emanuele Paci: University of Leeds
Martin Lepšík: CNRS
Robert J. C. Gilbert: University of Oxford
Ralf P. Richter: University of Leeds
David G. Jackson: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57866-8

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