The novel Jagged1/CD46 interaction: A prime target for immune modulation by viruses?

Devon Sheppard, Pat Whiteman, Gaelle Le Friec, Simon N. Waddington, Richard Smith, Teresa Melchionna, Claudia Kemper, James M. McDonnell, Penny A. Handford, Susan M. Lea

Research output: Contribution to journalMeeting abstractpeer-review


CD46 is a complement regulator and functions as cofactor in the factor I-mediated inactivation of C3b/C4b deposited on self-tissue. Importantly, CD46 is also costimulator/regulator for human Th1 induction and a receptor for several important pathogens including measles, herpes simplex and adenovirus. The ligands and their binding sites within CD46 are defined for the first two activities; complement activation fragments C3b/C4b bind to CCP2–4, whilst viral ligands commonly interact with domains CCP1–2. We have identified the Notch protein family member Jagged1 has as second physiological ligand for CD46. Using nuclear magnetic resonance spectroscopy and surface plasmon resonance, we have mapped the Jagged1 binding to an interaction surface comprised of CD46 CCP1–2. Thus Jagged1 binding to CD46 does not interfere with it's complement regulatory function. Further, we established the KD for the Jagged1/CD46 interaction at 8 μM, which is comparable to that of the CD46 and C3b/C4b interaction but, interestingly, an order of magnitude tighter than the Notch1/Jagged1 interaction. Furher, comparison of our data with structures of CCP1-2 bound to measles and adenovirus proteins implies that Jagged1-bound CD46 can not bind the viral ligands simultaneously, even where the surfaces involved are not-overlapping, without displacement of Jagged1 from CD46. Given that the CD46/Jagged-1 interaction is required for normal IFN-gproduction induction in vivo and that patients with defects with CD46 or Jagged1 suffer from recurrent viral infections, our data suggest that viruses may target CD46 CCP1-2 particularly to interfere with protective Th1 generation.
Original languageEnglish
Pages (from-to)1210-1211
Number of pages2
Issue number11
Publication statusPublished - Nov 2012


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