ORCID Profile
0000-0002-8810-0369
Current Organisations
Duke University
,
University of York
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Publisher: eLife Sciences Publications, Ltd
Date: 22-08-2019
DOI: 10.7554/ELIFE.46840
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.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-07-2014
DOI: 10.1126/SCITRANSLMED.3008705
Abstract: Uncharacterized proteins from the merozoite stage of Plasmodium falciparum provide new antigens for malaria blood-stage vaccine development.
Publisher: Elsevier BV
Date: 06-2019
Publisher: American Chemical Society (ACS)
Date: 20-10-2009
DOI: 10.1021/JA9053459
Abstract: This paper explores the contribution of solvation to the overall steric effects of S(N)2 reactions observed in solution. The reactions of chloride ion with a series of alkyl chloronitriles, RCH(CN)Cl (R = methyl, ethyl, isopropyl, tert-butyl) were investigated both experimentally and theoretically. These reactions serve as a model system for the parent reactions, Cl(-) + RCH(2)Cl, which are too slow to measure. Each additional substitution at the beta-carbon lowers the reactivity, clearly demonstrating a steric hindrance effect. The magnitude of the steric effect, however, is not significantly different in the gas phase and in solution. We conclude that the solvation energies of the corresponding S(N)2 transition states must be similar regardless of size of the substituent. This lack of size dependence in the current system is in sharp contrast with many other ionic systems such as ionization of simple alkyl alcohols, where solvation depends strongly on size. We propose that the weak size dependence results from the compensation between a direct shielding effect of the substituent and an indirect ionic solvation effect, which arises from the geometric perturbations introduced by the substitution. The conclusion is further supported by calculations using polarizable continuum models and QM/MM simulations.
Publisher: eLife Sciences Publications, Ltd
Date: 30-07-2019
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stephen Craig.