Structural basis for inhibition of complement C5 by the SSL7 protein from Staphylococcus aureus

Area of Science:

• Immunology
• Microbiology
• Structural Biology

Background:

• Staphylococcus aureus employs immune evasion strategies, including secreting the SSL7 protein.
• SSL7 protein binds both complement component 5 (C5) and immunoglobulin A (IgA).
• The precise mechanism and functional significance of SSL7 binding to C5 and IgA remain unclear.

Purpose of the Study:

• To elucidate the structural basis of SSL7 interaction with C5 and IgA.
• To determine the functional role of SSL7 in cross-linking C5 and IgA.
• To investigate the potential of SSL7-mediated inhibition as a therapeutic strategy.

Main Methods:

• Isolation of a stable IgA-SSL7-C5 complex.
• Determination of the crystal structure of the C5-SSL7 complex.
• Functional assays assessing complement component C5 cleavage, C5a production, bacteriolysis, and hemolysis.

Main Results:

• Crystal structure reveals SSL7's beta-grasp domain binds C5 away from the C5a cleavage site, leaving the OB domain free for IgA interaction.
• SSL7 facilitates IgA-dependent inhibition of convertase-mediated C5 cleavage.
• Inhibition of C5a production and bacteriolysis requires both C5 and IgA binding, while hemolysis inhibition is mediated by C5 binding alone.

Conclusions:

• SSL7 acts as a molecular bridge between C5 and IgA, contributing to Staphylococcus aureus immune evasion.
• The findings provide a structural and functional basis for developing targeted complement inhibitors.
• This approach selectively inhibits the formation of the membrane attack complex without disrupting essential C5a signaling functions.