AUTHOR=Dunphy Rhys W. , Wahid Ayla A. , Back Catherine R. , Martin Rebecca L. , Watts Andrew G. , Dodson Charlotte A. , Crennell Susan J. , van den Elsen Jean M. H. 

TITLE=Staphylococcal Complement Evasion Protein Sbi Stabilises C3d Dimers by Inducing an N-Terminal Helix Swap

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.892234

DOI=10.3389/fimmu.2022.892234

ISSN=1664-3224

ABSTRACT=<p><italic>Staphylococcus aureus</italic> is an opportunistic pathogen that is able to thwart an effective host immune response by producing a range of immune evasion molecules, including <italic>S. aureus</italic> binder of IgG (Sbi) which interacts directly with the central complement component C3, its fragments and associated regulators. Recently we reported the first structure of a disulfide-linked human C3d<sup>17C</sup> dimer and highlighted its potential role in modulating B-cell activation. Here we present an X-ray crystal structure of a disulfide-linked human C3d<sup>17C</sup> dimer, which undergoes a structurally stabilising N-terminal 3D domain swap when in complex with Sbi. These structural studies, in combination with circular dichroism and fluorescence spectroscopic analyses, reveal the mechanism underpinning this unique helix swap event and could explain the origins of a previously discovered N-terminally truncated C3dg dimer isolated from rat serum. Overall, our study unveils a novel staphylococcal complement evasion mechanism which enables the pathogen to harness the ability of dimeric C3d to modulate B-cell activation.</p>