Struktur und Funktionsanalyse der Wechselwirkungen zwischen Adenoviren und ihrem Zellrezeptor CD46
Zusammenfassung der Projektergebnisse
Adenoviruses are human pathogens and are also useful tools for gene delivery. A major advance was achieved in this project as we were able lo determine with high precision how adenoviruses bind to their receptor CD46 at the cell surface. The crystal structure of the adenovirus knob in complex with two domains of its receptor, CD46, shows that the receptor is in a profoundly altered conformation when interacting with its ligand. Such conformational change may prove to be conserved among the other pathogens that use CD46 as a receptor. Structural and functional data define with very high accuracy the exact atoms of the viral and cellular proteins that participate in the interaction. With this knowledge, one can now begin to understand how these viruses target their receptors, and this can also be used to understand other, related viral strains. It also becomes possible to intervene with the interaction, in an effort to develop molecules that block attachment of these viruses to cells. The discovery that adenoviruses alter the overall structure of their receptor CD46 was a big surprise for us. This was unexpected as no other virus to date has been found to alter their receptor structure in such a manner. Yet, our findings have significant implications for the development of anti-viral drugs, and also for understanding what events inside the cell might be affected by the conformational change seen in CD46. One scenario that we are currently pursuing is that the conformational change in CD46 leads to altered cellular signalling. Our data have been published in prestigious, highly competitive and internationally recognized journals. Nature Structural and Molecular Biology is a leading journal reporting on structurefuncfion studies. The Journal of Virology is the leading journal in virology. Moreover, the two publications in Journal of Virology were both chosen for the Spotlight feature by the editors. This feature highlights 5-6 publications in each issue. The article by Persson el al., 2009 was furthermore chosen for the cover of issue 4 of the Journal of Virology. In addilion, the work also led to a television interview of Dr. Arnberg in Sweden.
Projektbezogene Publikationen (Auswahl)
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(2007). Adenovirus type 11 binding alters the conformation of its receptor CD46. Nat. Struct. Mol. Biol. 14,164-166
Persson BD, Reiter DM, Marttila M, Mei YF, Casasnovas JM, Arnberg N, Stehle T
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(2007). Identification of CD46 binding sites within the adenovirus serotype 35 fiber knob. J. Virol. 81,12785-12795
Wang H, Liaw YC, Stone D, Kalyuzhniy O, Amiraslanov I, Tuve S, Verlinde CL, Shayakhmetov D, Stehle T, Roffler S, Lieber A
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(2008). In vitro and in vivo properties of adenovirus vectors with increased affinity to CD46. J. Virol. 82,10567-10579
Wang H, Liu Y, Li Z, Tuve S, Stone D, Kalyushniy O, Shayakhmetov D, Verlinde CL, Stehle T, McVey J, Baker A, Peng KW, Roffler S, Lieber A
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(2009). An arginine switch in the species B adenovirus determines high affinity engagement of the cellular receptor CD46. J. Virol. 83, 673-686
Persson DB, Muller S, Reiter DR, Schmitt BBT, Marttila M, Sumowski CV, Schweizer S, Scheu U, Ochsenfeld C, Arnberg N, Stehle T
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(2009). Specificity switching in virus-receptor complexes. Curr. Opin. Struct. Biol; 19:181-188
Stehle T, Casasnovas, JM
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(2010). Structure of adenovirus type 21 knob in complex with CD46 reveals key differences in receptor contacts among species B adenoviruses. J. Virol. 84, 3189-3200
Cupelli K, Müller S, Persson D, Scheu U, Arnberg N, Stehle T
