Nature Communications (Mar 2025)

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,
  • David G. Jackson

DOI
https://doi.org/10.1038/s41467-025-57866-8
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 18

Abstract

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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.