6R0X

The extracellular domain of G6b-B in complex with Fab fragment and DP12 heparin oligosaccharide.

6R0X の概要

• エントリーDOI: 10.2210/pdb6r0x/pdb
• 分子名称: antibody fab fragment heavy chain, antibody fab fragment light chain, Megakaryocyte and platelet inhibitory receptor G6b, ... (5 entities in total)
• 機能のキーワード: platelets, signaling, itim-receptor, g6b-b, heparin, blood clotting
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 131714.53

構造登録者

Ogg, D.J.,McMiken, H.J.,Howard, T.D. (登録日: 2019-03-13, 公開日: 2019-09-04, 最終更新日: 2024-10-23)

主引用文献

Vogtle, T.,Sharma, S.,Mori, J.,Nagy, Z.,Semeniak, D.,Scandola, C.,Geer, M.J.,Smith, C.W.,Lane, J.,Pollack, S.,Lassila, R.,Jouppila, A.,Barr, A.J.,Ogg, D.J.,Howard, T.D.,McMiken, H.J.,Warwicker, J.,Geh, C.,Rowlinson, R.,Abbott, W.M.,Eckly, A.,Schulze, H.,Wright, G.J.,Mazharian, A.,Futterer, K.,Rajesh, S.,Douglas, M.R.,Senis, Y.A.
Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.
Elife, 8:-, 2019

PubMed 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.

PubMed: 31436532
DOI: 10.7554/eLife.46840

実験手法

X-RAY DIFFRACTION (3.13 Å)