title: Structure of adenovirus type 21 knob in complex with CD46 reveals key differences in receptor contacts among species B adenoviruses.
abstract: The complement regulation protein CD46 is the primary attachment receptor for most species B adenoviruses (Ads). However, significant variability exists in sequence and structure among species B Ads in the CD46-binding regions, correlating with differences in affinity. Here, we report a structure-function analysis of the interaction of the species B Ad21 knob with the two N-terminal repeats SCR1 and SCR2 of CD46, CD46-D2. We have determined the structures of the Ad21 knob in its unliganded form as well as in complex with CD46-D2, and we compare the interactions with those observed for the Ad11 knob-CD46-D2 complex. Surface plasmon resonance measurements demonstrate that the affinity of Ad21 knobs for CD46-D2 is 22-fold lower than that of the Ad11 knob. The superposition of the Ad21 and Ad11 knob structures in complex with CD46-D2 reveals a substantially different binding mode, providing an explanation for the weaker binding affinity of the Ad21 knob for its receptor. A critical difference in both complex structures is that a key interaction point, the DG loop, protrudes more in the Ad21 knob than in the Ad11 knob. Therefore, the protruding DG loop does not allow CD46-D2 to approach the core of the Ad21 knob as closely as in the Ad11 knob-CD46-D2 complex. In addition, the engagement of CD46-D2 induces a conformational change in the DG loop in the Ad21 knob but not in the Ad11 knob. Our results contribute to a more profound understanding of the CD46-binding mechanism of species B Ads and have relevance for the design of more efficient gene delivery vectors.
authors.affiliation: Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Cupelli
authors.forename: Steffen
authors.initials: S
authors.lastname: Müller
authors.forename: B David
authors.initials: BD
authors.lastname: Persson
authors.forename: Marco
authors.initials: M
authors.lastname: Jost
authors.forename: Niklas
authors.initials: N
authors.lastname: Arnberg
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
mesh_terms: D000260:Adenoviruses, Human / Q000737:chemistry* / Q000145:classification / Q000502:physiology; D000595:Amino Acid Sequence; D036022:Capsid Proteins / Q000737:chemistry*; D051916:Membrane Cofactor Protein / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011991:Receptors, Virus / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D053585:Virus Attachment
chemical_list: D036022:Capsid Proteins; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus