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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B Timo Vögtle , Sumana Sharma , Jun Mori , Zoltan Nagy , Daniela Semeniak , Cyril Scandola , Mitchell J. Geer , Christopher W. Smith , Jordan Lane , Scott Pollack , Riitta Lassila , Annukka Jouppila , Alastair J. Barr , Derek J. Ogg , Tina D. Howard , Helen J. Mcmiken , Juli Warwicker , Catherine Geh , Rachel Rowlinson , W. Mark Abbott , Anita Eckly , Harald Schulze , Gavin J. Wright , Alexandra Mazharian , Klaus Futterer , Sundaresan Rajesh , Michael R. Douglas , Yotis A. Senis Elife 8 DOI: 10.7554/eLife.46840 Diamond Proposal Number(s): [20026] Open Access Show Abstract ▼ 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.	Aug 2019

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I03-Macromolecular Crystallography

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