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Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B

DOI: 10.7554/eLife.46840 DOI Help

Authors: Timo Vögtle (University of Birmingham) , Sumana Sharma (Wellcome Sanger Institute) , Jun Mori (University of Birmingham) , Zoltan Nagy (University of Birmingham) , Daniela Semeniak (University Hospital Würzburg) , Cyril Scandola (Université de Strasbourg) , Mitchell J. Geer (University of Birmingham) , Christopher W. Smith (University of Birmingham) , Jordan Lane (Sygnature Discovery Limited) , Scott Pollack (Sygnature Discovery Limited) , Riitta Lassila (University of Helsinki) , Annukka Jouppila (Helsinki University Hospital Research Institute) , Alastair J. Barr (University of Westminster) , Derek J. Ogg (Peak Proteins Limited) , Tina D. Howard (Peak Proteins Limited) , Helen J. Mcmiken (Peak Proteins Limited) , Juli Warwicker (Peak Proteins Limited) , Catherine Geh (Peak Proteins Limited) , Rachel Rowlinson (Peak Proteins Limited) , W. Mark Abbott (Peak Proteins Limited) , Anita Eckly (Université de Strasbourg) , Harald Schulze (University Hospital Würzburg) , Gavin J. Wright (Wellcome Trust Sanger Institute) , Alexandra Mazharian (University of Birmingham) , Klaus Futterer (University of Birmingham) , Sundaresan Rajesh (University of Birmingham) , Michael R. Douglas (University of Birmingham) , Yotis A. Senis (University of Birmingham)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Elife , VOL 8

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 20026

Open Access Open Access

Abstract: The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

Journal Keywords: platelets; ITIM-receptor; G6b-B; heparan sulfate; heparin, perlecan; signaling; tyrosine phosphatases

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography