Molecular insights into intercellular adhesion in Staphylococcal biofilms
Andrew B. Herr, Ph.D.
Divisions of Immunobiology & Infectious Diseases
Cincinnati Children’s Hospital Medical Center
Staphylococcal species are responsible for approximately two-thirds of all hospital-acquired infections. A major challenge with Staphylococci is their propensity to form biofilms, which are surface-adherent colonies that are highly resistant to antibiotic action or host immune responses. The Accumulation-Associated Protein (Aap) from S. epidermidis plays a critical role in holding bacterial cells together within a biofilm. Aap is a large, multi-functional cell surface protein that can mediate attachment to host cells but is also responsible for intercellular adhesion between bacterial cells within a biofilm. The C-terminal portion of Aap contains 5 to 17 nearly-identical tandem B-repeats, which are responsible for the adhesive function of Aap. We have shown using biophysical and crystallographic approaches that the B-repeats of Aap self-assemble in the presence of Zn2+. The two protein chains coordinate Zn2+ in trans to form an extended, anti-parallel dimer. The protein fold is quite unusual, comprising elongated three-stranded b-sheets separated by regions of twisted coil. The protein lacks a classic hydrophobic core, but instead exhibits a ‘hydrophobic stack’ at each inter-domain junction that stabilizes the fold. Further characterization has revealed subtypes of the B-repeat within Aap that define a preferred assembly code for the full-length protein. These investigations of the molecular basis for intercellular adhesion have opened the door to new therapeutic approaches to inhibit formation of staphylococcal biofilms.