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6r0x

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

Structural highlights

6r0x is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.13Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

G6B_HUMAN The disease is caused by variants affecting the gene represented in this entry.

Function

G6B_HUMAN Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production (PubMed:12665801, PubMed:17311996, PubMed:27743390). Inhibits platelet aggregation and activation by agonists such as ADP and collagen-related peptide (PubMed:12665801). This regulation of megakaryocate function as well as platelet production ann activation is done through the inhibition (via the 2 ITIM motifs) of the receptors CLEC1B and GP6:FcRgamma signaling (PubMed:17311996). Appears to operate in a calcium-independent manner (PubMed:12665801).^[1] ^[2] ^[3] Isoform B, displayed in this entry, is the only isoform to contain both a transmembrane region and 2 immunoreceptor tyrosine-based inhibitor motifs (ITIMs) and, thus, the only one which probably has a role of inhibitory receptor. Isoform A may be the activating counterpart of isoform B.^[4]

Publication Abstract from PubMed

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.

Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.,Vogtle T, Sharma S, Mori J, Nagy Z, Semeniak D, Scandola C, Geer MJ, Smith CW, Lane J, Pollack S, Lassila R, Jouppila A, Barr AJ, Ogg DJ, Howard TD, McMiken HJ, Warwicker J, Geh C, Rowlinson R, Abbott WM, Eckly A, Schulze H, Wright GJ, Mazharian A, Futterer K, Rajesh S, Douglas MR, Senis YA Elife. 2019 Aug 22;8:e46840. doi: 10.7554/eLife.46840. PMID:31436532^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J. Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nat Biotechnol. 2003 May;21(5):566-9. PMID:12665801 doi:10.1038/nbt810
↑ Newland SA, Macaulay IC, Floto AR, de Vet EC, Ouwehand WH, Watkins NA, Lyons PA, Campbell DR. The novel inhibitory receptor G6B is expressed on the surface of platelets and attenuates platelet function in vitro. Blood. 2007 Jun 1;109(11):4806-9. PMID:17311996 doi:10.1182/blood-2006-09-047449
↑ Melhem M, Abu-Farha M, Antony D, Madhoun AA, Bacchelli C, Alkayal F, AlKhairi I, John S, Alomari M, Beales PL, Alsmadi O. Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia. Eur J Haematol. 2017 Mar;98(3):218-227. PMID:27743390 doi:10.1111/ejh.12819
↑ de Vet EC, Aguado B, Campbell RD. G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2. J Biol Chem. 2001 Nov 9;276(45):42070-6. PMID:11544253 doi:10.1074/jbc.M103214200
↑ Vögtle T, Sharma S, Mori J, Nagy Z, Semeniak D, Scandola C, Geer MJ, Smith CW, Lane J, Pollack S, Lassila R, Jouppila A, Barr AJ, Ogg DJ, Howard TD, McMiken HJ, Warwicker J, Geh C, Rowlinson R, Abbott WM, Eckly A, Schulze H, Wright GJ, Mazharian A, Fütterer K, Rajesh S, Douglas MR, Senis YA. Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. Elife. 2019 Aug 22;8:e46840. PMID:31436532 doi:10.7554/eLife.46840