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A research grant of £110,951 has been awarded to Dr Alan Stewart and Dr Imre Lengyel (UCL Institute of Ophthalmology) from Fight for Sight to carry out a new 2-year study entitled “Identifying the hydroxyapatite interactome: clarifying the involvement of serum proteins in the formation of sub-retinal pigment epithelial (RPE) deposits”. A major feature of the ageing retina is the thickening of Bruch’s membrane and the formation of sub-retinal pigment epithelial (RPE) deposits that can block metabolic exchange between the choroidal blood circulation and the retina leading to sensory retinal degeneration and eventually to age-related macular degeneration (AMD), a major cause of visual impairment and blindess in older adults (>50 years). Recently, Thompson et al. reported the existence of small (0.5-20 μm diameter) protein-binding hydroxyapatite (HAP) spherules within sub-RPE deposits isolated from AMD-affected individuals (see link). This suggests that the spherules may provide nucleation sites for sub-RPE deposit formation, where the initiation, growth and retention of deposits are controlled by the binding of proteins present in the sub-RPE space to the spherules. In the funded study, HAP-binding proteins in the plasma of genotyped late-stage AMD patients will be isolated and quantitatively identified and biochemically characterised.

A research grant of £191,250 has been awarded to Dr Alan Stewart from the British Heart Foundation to carry out a new 3-year study entitled “Role of zinc in controlling histidine-rich glycoprotein (HRG) complex formation: Implications for the development of thrombotic complications”. This work will advance current knowledge of the structure and function of HRG, a key molecule involved in controlling coagulation, and its regulation of haemostasis in health and disease. In addition, the project will evaluate a potentially novel zinc-dependent haemopathological mechanism in diabetes patients stemming from elevated plasma FFA levels and modulation of HRG functioning. The study is a collaboration between investigators at the University of St Andrews (Dr Stewart, Dr Samantha Pitt and Prof. James Naismith) and the University of Leeds (Dr Ramzi Ajjan).

Histidine-rich glycoprotein (HRG) is a plasma protein that regulates a number of biological processes in the blood including coagulation, through its ability to bind and neutralize heparins. HRG contains a distinctive histidine-rich region that associates with zinc ions (Zn²⁺) to stimulate HRG-heparin complex formation. Under normal conditions the majority of Zn²⁺ in plasma associates with serum albumin. However, clinically high levels of free fatty acid (FFA) allosterically disrupt the major Zn²⁺-binding site on serum albumin and are associated with an increased risk of thrombotic complications. The Stewart group report in the Journal of Thrombosis and Haemostasis that increased levels of circulatory fatty acids are likely to increase the proportion of plasma Zn²⁺ associated with HRG. In this study the Zn²⁺-binding properties of HRG and the formation of HRG-heparin complexes in the presence of different Zn²⁺ concentrations were investigated. Furthermore, the binding of Zn²⁺ to serum albumin was examined in the presence of various concentrations of myristate by ITC. Speciation modeling of plasma Zn²⁺ based upon the data obtained from these experiments suggests that FFA-mediated displacement of Zn²⁺ from serum albumin is likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels – Full text is available online.

Many congratulations to Omar who passed his PhD viva today!

A new VIZIB (Virtual Institute of Zinc Biology) website has been launched, with help of the Royal Society of Chemistry as part of the Zinc-net European Cooperation in Science and Technology (COST) Action chaired by Prof. Nicola Lowe (UCLAN). The purpose of the new site is for researchers interested in the study of zinc to share ideas and establish collaborations. The site can be accessed here (please note that registration is required).

We report the first structural characterisation of histidine-rich glycoprotein, an important plasma adaptor protein following elucidation of the 1.93 Å X-ray crystal structure of the protein’s N2 domain (PDB: 4CCV). This region forms part of an important ligand interaction site on the molecule, that binds a range of molecules including the natural anti-coagultant, heparin. The structure, solved in collaboration with Prof. Jim Naismith’s laboratory revealed the presence of an S-glutathionyl adduct, which has implications for the control of angiogenesis. – Open access version in Europe PMC.