4zdg | pdb_00004zdg
Structure of the Adenovirus 14p1 knob domain
Structural highlights
FunctionPublication Abstract from PubMedWe recently discovered that DSG2 is a receptor for human adenovirus species B serotypes Ad3, 7, 11, and 14. Ad3 is considered to be a widely distributed human pathogen. Ad3 binding to DSG2 triggers the transient opening of epithelial junctions. Here we further delineate the mechanism that leads to DSG2 mediated epithelial junction opening in cells exposed to Ad3 and recombinant Ad3 fiber proteins. We identified an Ad3 fiber knob-dependent pathway that involves the phosphorylation of MAP kinases triggering the activation of the matrix-metalloproteinase ADAM17. ADAM17 in turn cleaves the extracellular domain of DSG2 that links epithelial cells together. The shed DSG2 domain can be detected in cell culture supernatant and also in serum of mice with established human xenograft tumors. We then extended our studies to Ad14 and Ad14P1. Ad14 is an important research and clinical object, because of the recent appearance of a new, more pathogenic strain (Ad14P1). In a human epithelial cancer xenograft model, Ad14P1 showed more efficient viral spread and oncolysis than Ad14. Here we tested the hypothesis whether a mutation in the Ad14P1 fiber knob could account for the differences between the two strains. While our X-ray crystallography studies suggested an altered 3D structure of the Ad14P1 fiber knob in the F-G loop region, this did not significantly change the fiber knob affinity to DSG2 nor the intracellular signaling and DSG2 shedding in epithelial cancer cells. IMPORTANCE: A number of widely distributed adenoviruses use the epithelial junction protein DSG2 as a receptor for infection and lateral spread. Interaction with DSG2 not only allows the virus to enter cells but also to open epithelial junctions which form a physical barrier to virus spread. Our study elucidates the mechanism beyond virus triggered junction opening with a focus on adenovirus serotype 3. Ad3 binds to DSG2 with its fiber knob domain and triggers intracellular signaling that culminates in the cleavage of the extracellular domain of DSG2 thereby disrupting DSG2 homodimers between epithelial cells. We confirmed this pathway with a second DSG2-interacting serotype, Ad14 and its recently emerged stain Ad14P1. These new insights in basic adenovirus biology can be employed to develop novel drugs to treat adenovirus infection as well as be used as tools for gene delivery into epithelial tissues or epithelial tumors. Intracellular signaling and desmoglein 2 shedding triggered by human adenoviruses Ad3, Ad14, and Ad14P1.,Wang H, Ducournau C, Saydaminova K, Richter M, Yumul R, Ho M, Carter D, Zubieta C, Fender P, Lieber A J Virol. 2015 Aug 19. pii: JVI.01425-15. PMID:26292319[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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