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Adenovirus type 11 binding alters the conformation of its receptor CD46.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
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2007 (Engelska)Ingår i: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 14, nr 2, s. 164-166Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Adenoviruses (Ads) are important human pathogens and valuable gene delivery vehicles. We report here the crystal structure of the species B Ad11 knob complexed with the Ad11-binding region of its receptor CD46. The conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. This mechanism of interaction is likely to be conserved among many pathogens that target CD46 or related molecules.

Ort, förlag, år, upplaga, sidor
2007. Vol. 14, nr 2, s. 164-166
Identifikatorer
URN: urn:nbn:se:umu:diva-20700DOI: 10.1038/nsmb1190PubMedID: 17220899OAI: oai:DiVA.org:umu-20700DiVA, id: diva2:209364
Tillgänglig från: 2009-03-24 Skapad: 2009-03-24 Senast uppdaterad: 2018-06-09
Ingår i avhandling
1. Cellular receptors for species B adenoviruses
Öppna denna publikation i ny flik eller fönster >>Cellular receptors for species B adenoviruses
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Adenoviruses belong to the most common human pathogens. The severity of infection varies greatly, from subclinical to lethal, depending on the virus type and immune status of the infected host. The 51 known human adenovirus serotypes are divided into six species (A-F) based on characteristics such as tropism. Species B adenoviruses, which are the subjects of this thesis, are further divided into subspecies B:1 that contains Ad3, Ad7, Ad16, Ad21 and Ad50 and subspecies B:2 that contains Ad11, Ad14, Ad34 and Ad35. Species B adenoviruses primarily cause ocular and respiratory tract infections, but certain serotypes (Ad11, Ad34 and Ad35) are also associated with renal disease.

The main aim of this thesis was to identify and characterize cellular receptors for species B adenoviruses. This will ultimately help to understand the diverse tropism shown by different adenoviruses and perhaps contribute to development of antivirals. Also, since adenoviruses are among the most commonly used vector for gene therapy it is of importance to characterize the initial steps of adenovirus life cycle.

Members of species B adenoviruses have been shown to utilize both the complement regulating membrane cofactor protein (MCP), i.e. CD46, and a still unknown receptor. CD80 and CD86, usually found on antigen-presenting cells, have also been suggested as receptors

We found first that Ad11 used CD46 as a cellular receptor on respiratory A549 cells, and subsequently that CD46 is a cellular receptor for all species B adenovirus serotypes, except for adenovirus types 3 and 7, using cells that represent the tropism of species B adenoviruses, i.e. respiratory, conjunctival and renal epithelial cells.

We further compared the relative roles of CD46 with CD80 and CD86 using cells that represent species B adenovirus tropism. Using soluble candidate receptors and antibodies against corresponding receptors to challenge virus binding to and infection of cells, we found that on these cells, CD46 is a cellular receptor for all species B adenoviruses except Ad3 and Ad7, and that CD80 and CD86 do not play an important role.

We have further pinpointed the interaction site for Ad11 on CD46 by X-ray crystallography. The extracellular region of CD46 contains four short consensus repeats (SCR1-4) of which the outermost N-terminal SCR1 and SCR2 mediate binding to Ad11. This interaction was confirmed by inhibiting infection and binding of Ad11 to A549 cells using soluble SCR1-2 fragments. Surprisingly the conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. Viral proteins can sometimes undergo large conformational changes upon receptor binding, but this is, to the best of our knowledge, the first example of a virus protein dramatically changing the overall structure of its receptor. CD46 serves as a receptor for a large number of viral and bacterial pathogens and it is structurally and functionally related to other viral receptors such as CD21 and CD55. The mode of interaction presented here may serve as a conceptual framework for studies of many other receptors that are constructed from SCR domains.

Ort, förlag, år, upplaga, sidor
Umeå: Klinisk mikrobiologi, 2007. s. 72
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1123
Nyckelord
Adenovirus, CD46, CD80, CD86, Species B, Receptor, Internalization, Infection, Tropism
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-1351 (URN)978-91-7264-409-0 (ISBN)
Disputation
2007-10-05, Betula, 6M, NUS, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2007-09-17 Skapad: 2007-09-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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