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.

Astbury Centre for Structural Molecular Biology University of Leeds Leeds LS2 9JT UK

Bragg Centre for Materials Research University of Leeds Leeds LS2 9JT UK

CERMAV Université Grenoble Alpes CNRS 38000 Grenoble France

CIC biomaGUNE Paseo Miramon 182 20014 Donostia San Sebastián Spain

Department of Biochemistry and Physiology University of Oklahoma Health Sciences Center Oklahoma City OK 73126 USA

Department of Clinical Microbiology Umeå University 90185 Umeå Sweden

Dipartimento di Fisica e Astronomia Università di Bologna 40127 Bologna Italy

Division of Structural Biology Wellcome Trust Centre for Human Genetics University of Oxford Roosevelt Drive Oxford OX3 7BN UK

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences 16610 Prague 6 Czech Republic

L1 60 Laboratory Block University of Hong Kong 21 Sassoon Road Hong Kong China

Medical Research Council Translational Immune Discovery Unit MRC Weatherall Institute of Molecular Medicine University of Oxford Oxford OX3 9DS UK

School of Biomedical Sciences Faculty of Biological Sciences University of Leeds Leeds LS2 9JT UK

School of Physics and Astronomy Faculty of Engineering and Physical Sciences University of Leeds Leeds LS2 9JT UK

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