Bubeck, Doryen - Imperial College London - Department of Life Sciences, Biochemistry and Biotechnology

个人简介

Doryen Bubeck received her PhD in Biophysics from Harvard University in 2005 where she used cryo-electron micrsocopy to investigate the cell entry mechanism of poliovirus. As an EMBO postdoctoral fellow and Cancer Research Institute Fellow at the University of Oxford, she continued to explore the structures of membrane proteins, focusing on the complement immune pathway. A recent highlight (Hadders & Bubeck et al., Cell Rep. 2012) is the discovery that complement components associate through a sideways alignment of their central MAC-perforin domains (MACPF). These results provide a structural framework for understanding the complex protein associations underlying activation of this innate immune effector. Doryen Bubeck is a lecturer in Structural Biology within the Department of Life Sciences and recipient of a Cancer Research UK Career Establishment Award. Her current research adopts an integrated structural approach merging cryo-electron microscopy and Xray crystallography to investigate the role of membrane proteins in host-pathogen interactions. She aims to investigate how membrane attack complex (MAC) pore formation is controlled, a process important for fighting infections and preventing complement-mediated tissue damage.

研究领域

Complement is an important component of the immune system that kills microbes by making pores in cell membranes. Host cells are protected from bystander damage by receptors that block pore assembly and prevent membrane insertion. Some bacteria secrete pore-forming toxins that hijack these immune receptors to promote their own pore formation, contributing to their pathogenicity. Cancer cells also manipulate this protection mechanism to evade the complement response during antibody-based immunotherapy treatments. The main objective of our research is to use structural biology to characterize the 3D structure of pore-forming proteins with immune receptors in model membranes. This research addresses biological questions relevant to understanding a mechanism of immunity and provides a strong foundation for the development of future antibiotics and cancer immunotherapies.

近期论文

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Boyd C, Parsons ES, Smith RAG, Seddon JM, Ces O, Bubeck Det al., Disentangling the roles of cholesterol and CD59 in intermedilysin pore formation, Scientific Reports, ISSN: 2045-2322 Bubeck DA, Dunstone M, Bayly-Jones C, The mystery behind membrane insertion: a review of the complement membrane attack complex, Philosophical Transactions of the Royal Society B: Biological Sciences, ISSN: 1471-2970 Morgan BP, Serna M, Bubeck D, 2016, Complex beauty complements membrane attack, Publisher: ELSEVIER GMBH, URBAN & FISCHER VERLAG, Pages: 1194-1194, ISSN: 0171-2985 Morgan BP, Walters D, Serna M, Bubeck Det al., 2016, Terminal complexes of the complement system: new structural insights and their relevance to function., Immunol Rev, Vol: 274, Pages: 141-151 Serna M, Giles JL, Morgan BP, Bubeck Det al., 2016, Structural basis of complement membrane attack complex formation, NATURE COMMUNICATIONS, Vol: 7, ISSN: 2041-1723 Taylor JD, Hawthorne WJ, Lo J, Dear A, Jain N, Meisl G, Andreasen M, Fletcher C, Koch M, Darvill N, Scull N, Escalera-Maurer A, Sefer L, Wenman R, Lambert S, Jean J, Xu Y, Turner B, Kazarian SG, Chapman MR, Bubeck D, de Simone A, Knowles TPJ, Matthews SJet al., 2016, Electrostatically-guided inhibition of Curli amyloid nucleation by the CsgC-like family of chaperones, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322 Bubeck D, 2015, Unraveling Structural Polymorphism of Amyloid Fibers, STRUCTURE, Vol: 23, Pages: 10-11, ISSN: 0969-2126 Guenther C, Kind B, Reijns MAM, Berndt N, Martinez-Bueno M, Wolf C, Tuengler V, Chara O, Lee YA, Huebner N, Bicknell L, Blum S, Krug C, Schmidt F, Kretschmer S, Koss S, Astell KR, Ramantani G, Bauerfeind A, Morris DL, Graham DSC, Bubeck D, Leitch A, Ralston SH, Blackburn EA, Gahr M, Witte T, Vyse TJ, Melchers I, Mangold E, Noethen MM, Aringer M, Kuhn A, Luethke K, Unger L, Bley A, Lorenzi A, Isaacs JD, Alexopoulou D, Conrad K, Dahl A, Roers A, Alarcon-Riquelme ME, Jackson AP, Lee-Kirsch MAet al., 2015, Defective removal of ribonucleotides from DNA promotes systemic autoimmunity, JOURNAL OF CLINICAL INVESTIGATION, Vol: 125, Pages: 413-424, ISSN: 0021-9738 Bubeck D, 2014, The Making of a Macromolecular Machine: Assembly of the Membrane Attack Complex, BIOCHEMISTRY, Vol: 53, Pages: 1908-1915, ISSN: 0006-2960 Johnson S, Brooks NJ, Smith RAG, Lea SM, Bubeck Det al., 2013, Structural Basis for Recognition of the Pore-Forming Toxin Intermedilysin by Human Complement Receptor CD59, CELL REPORTS, Vol: 3, Pages: 1369-1377, ISSN: 2211-1247 Hadders MA, Bubeck D, Roversi P, Hakobyan S, Forneris F, Morgan BP, Pangburn MK, Llorca O, Lea SM, Gros Pet al., 2012, Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9, CELL REPORTS, Vol: 1, Pages: 200-207, ISSN: 2211-1247 Bubeck D, Reijns MAM, Graham SC, Astell KR, Jones EY, Jackson APet al., 2011, PCNA directs type 2 RNase H activity on DNA replication and repair substrates, NUCLEIC ACIDS RESEARCH, Vol: 39, Pages: 3652-3666, ISSN: 0305-1048 Bubeck D, Roversi P, Donev R, Morgan BP, Llorca O, Lea SMet al., 2011, Structure of Human Complement C8, a Precursor to Membrane Attack, JOURNAL OF MOLECULAR BIOLOGY, Vol: 405, Pages: 325-330, ISSN: 0022-2836 Chen S, Bubeck D, MacDonald BT, Liang W-X, Mao J-H, Malinauskas T, Llorca O, Aricescu AR, Siebold C, He X, Jones EYet al., 2011, Structural and Functional Studies of LRP6 Ectodomain Reveal a Platform for Wnt Signaling, DEVELOPMENTAL CELL, Vol: 21, Pages: 848-861, ISSN: 1534-5807 Reijns M, Bubeck D, Gibson LCD, Graham SC, Leitch A, Baillie GS, Jones EY, Jackson APet al., 2011, Using crystallography and biophysics to understand mutations in the Aicardi-Goutieres Syndrome Ribonuclease H2 enzyme, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S30-S30, ISSN: 0022-2593 Reijns MAM, Bubeck D, Gibson LCD, Graham SC, Baillie GS, Jones EY, Jackson APet al., 2011, The Structure of the Human RNase H2 Complex Defines Key Interaction Interfaces Relevant to Enzyme Function and Human Disease, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 10530-10539, ISSN: 0021-9258 Bubeck D, Filman DJ, Kuzmin M, Fuller SD, Hogle JMet al., 2008, Post-imaging fiducial markers aid in the orientation determination of complexes with mixed or unknown symmetry, JOURNAL OF STRUCTURAL BIOLOGY, Vol: 162, Pages: 480-490, ISSN: 1047-8477 Roversi P, Bubeck D, Donev R, Hepburn N, Jones EY, Morgan BP, Lea Set al., 2008, Single-particle electron microscopy reconstruction of the structure of complement component 8 (C8) at 23 angstrom resolution, 22nd International Complement Workshop, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 4121-4121, ISSN: 0161-5890 Bostina M, Bubeck D, Schwartz C, Nicastro D, Filman DJ, Hogle JMet al., 2007, Single particle cryoelectron tomography characterization of the structure and structural variability of poliovirus-receptor-membrane complex at 30 angstrom resolution, JOURNAL OF STRUCTURAL BIOLOGY, Vol: 160, Pages: 200-210, ISSN: 1047-8477 Bubeck D, Roversi P, Donev R, Hepburn NJ, Leath K, Jones EY, Morgan BP, Lea SMet al., 2007, Structural analysis of the soluble C5b-9 complex using cryoelectron microscopy, 11th European Meeting on Complement in Human Disease, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 3981-3982, ISSN: 0161-5890