SAXCESS · Structure-function analysis of the human plasma glycoprotein afamin, a potential drug target in the treatment of metabolic syndrome.""

Structure-function analysis of the human plasma glycoprotein afamin, a potential drug target in the treatment of metabolic syndrome.

Project Background and Aims. The IIF project PIIF-GA-2011-300025 (SAXCESS - Structure-function of Afamin by X-ray Crystallography Enabled Structure Solution) was a collaborative effort between the incoming international fellow (IF) Bernhard Rupp, an experienced structural biologist, crystallographer, and text book author from California, USA, with the group of the host scientist in charge, Prof. Hans Dieplinger, Associate Professor at the Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck). The scientific accomplishments of the SAXCESS project have paved the path towards determination and analysis of the molecular structure of human glycoprotein afamin, a vitamin E transporting protein and biomarker, whose elevated levels are associated with all major lifestyle-related symptoms of metabolic syndrome such as high blood glucose, hyperlipemia, obesity and high blood pressure. An additional objective of the project was to bring new technologies and ideas to the European Research Area and to train students and postdoctoral fellows for internationally competitive work in structural biology. Scientific accomplishments. The SAXCESS project was a technically challenging, high risk project and required a multidisciplinary collaboration, ranging in areas of expertise from medical genetics, cell biology, medicinal biochemistry (host expertise), to structural biology, biophysics, biomolecular crystallography, and structural bioinformatics (IF expertise). Despite its high clinical relevance as a biomarker for metabolic syndrome, almost nothing was known about the relation between structure and transport function of the glycoprotein afamin. We have generated multiple variants of the protein with different degrees of glycosylation and have found that afamin has the capability of transporting many different low molecular weight molecules in the bloodstream. Afamin therefore can have substantial impact on therapeutic drug clearance and affect the levels of drugs that need to be administered when afamin levels are increased. Because afamin itself is very hard to crystallize for X-ray crystallographic structure studies, we have also used fragments of antibodies against afamin as scaffolding agents during crystallization. In addition, we developed a novel approach to introduced low-solubility ligands and drugs through lipid cubic phase crystallization, a method that can have significant general impact for structural studies of protein targets with hydrophobic, low solubility molecules and drugs. Our studies have revealed that afamin is a much more varied and complex transporter and biomarker than anticipated, and its transport properties are suspected to impact therapeutic drug clearance. A follow-up study with the aim to elucidate relation between the structure of afamin and its lipophilic drug transport properties has been submitted to the Austrian Science Foundation (FWF). Socio-economic impact of knowledge transfer and contribution to European excellence and European competitiveness. The associated transfer of knowledge in the methods of structure determination opened an entirely new direction of research at the European host laboratory and established the basis for a long-term collaboration between applicant and hosting laboratory on potential therapeutic applications. Significant knowledge transfer activities were accomplished through introduction of multiple new strategic technologies in the host institution as detailed in the full report. Tutoring and technical guidance of high school students, graduate students and postdoctoral students in the host laboratory and other departments of the host institution also contributed to enhanced competitiveness of the European Research Area. Additional activities accomplished are nine peer reviewed publications, multiple invited lectures at leading European Research Institutions, and training and dissemination of knowledge in the ERA through participation and tutoring in seven workshop by the incoming researcher. A copy "Biomolecular Crystallography: Principles, Practice and Applications to Structural Biology" was awarded by the author for the best poster or presentation at these workshops and at the 23rd Congress and General Assembly of the International Union of Crystallography, Montreal, Canada, August 5-12, 2014. In celebration of the International Year of Crystallography 2014, additional public outreach material has been prepared and is available at http://www.ruppweb.org/iycr/IYCr_2014.htm.

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