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Janus Asbjørn Schatz-Jakobsen: Structural insight into the inhibition of the terminal pathway of the complement system

PhD defence, Friday 16 September 2016. Janus Asbjørn Schatz-Jakobsen.

[Translate to English:] Janus Asbjørn Schatz-Jakobsen

During his PhD studies, Janus Asbjørn Schatz-Jakobsen investigated proteins of the terminal pathway of the human complement system. The complement system is an important effector arm of the innate immune system and acts as a first line defense against invading pathogens and altered self-cells. The terminal pathway of complement is initiated when the so-called C5 convertases recognizes and cleaves the complement protein C5 into C5b and C5a. C5b and C5a induce the assembly of a membrane pore forming complex and stimulates pro-inflammatory events, respectively. Dysregulation of this cleavage event and of the downstream effector functions correlates with development of diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The monoclonal antibody eculizumab developed by Alexion Pharmaceuticals, binds the C5 molecule and inhibits the C5 cleavage, and is used to treat patients suffering from PNH and aHUS.

Using X-ray crystallography Janus Asbjørn Schatz-Jakobsen determined the crystal structure of C5 bound to a Fab-fragment of eculizumab. This structure describes the inhibitory mechanism of eculizumab and contributes to the understanding of how the C5 molecule is recognized and cleaved by the C5 convertases.

The PhD degree was completed at the Department of Molecular Biology and Genetics, Science and Technology, Aarhus University.

This résumé was prepared by the PhD student.

Time: Friday 16 September 2016 at 13.15
Place: Building 1593, room 012, The Lecture Theatre, iNANO House, Gustav Wieds Vej 14, Aarhus University, 8000 Aarhus C
Title of dissertation: Structural insight into the inhibition of complement C5 cleavage and structural and functional investigation of C5a anaphylatoxins
Contact information: Janus Asbjørn Schatz-Jakobsen, e-mail: janusasj@mbg.au.dk, tel.: +45 28734784
Members of the assessment committee:
Associate Professor Suzan Rooijakkers, Infection and Immunity Center, Utrecht Universitet
Associate Professor Osman Asghar Mirza, Biostructural Research, Faculty of Health, University of Copenhagen
Associate Professor Ditlev Egeskov Brodersen (chair), Department of Molecular Biology and Genetics, Aarhus University
Main supervisor:
Professor Gregers Rom Andersen, Department of Molecular Biology and Genetics, Aarhus University
Language: The PhD dissertation will be defended in English

The defence is public. The dissertation is available for reading at the Graduate School of Science and Technology/GSST, Ny Munkegade 120, building 1520, rooms 128-134, 8000 Aarhus C.