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Infection and Immunity, July 2008, p. 3273-3280, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00366-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Interaction of Porphyromonas gingivalis with Oral Streptococci Requires a Motif That Resembles the Eukaryotic Nuclear Receptor Box Protein-Protein Interaction Domain{triangledown}

Carlo Amorin Daep,1 Richard J. Lamont,2 and Donald R. Demuth1*

Department of Periodontics, Endodontics and Dental Hygiene, University of Louisville, Louisville, Kentucky,1 Department of Oral Biology, University of Florida, Gainesville, Florida2

Received 21 March 2008/ Returned for modification 29 April 2008/ Accepted 4 May 2008

Porphyromonas gingivalis initially colonizes the oral cavity by interacting with organisms in supragingival plaque, such as the oralis group of oral streptococci. This interaction involves the association of the streptococcal antigen I/II with the minor fimbrial antigen (Mfa1) of P. gingivalis. Our previous studies showed that a peptide (BAR) derived from antigen I/II inhibits P. gingivalis adherence and subsequent biofilm formation on streptococcal substrates. In addition, screening a combinatorial peptide library identified select amino acid substitutions in the NITVK active region of BAR that increased the adherence of P. gingivalis to streptococci. Here we report that incorporating these residues in a synthetic peptide results in more-potent inhibition of P. gingivalis adherence and biofilm formation (I50 [50% inhibition] at 0.52 µM versus I50 at 1.25 µM for BAR). In addition, a second structural motif in BAR, comprised of the amino acids KKVQDLLKK, was shown to contribute to P. gingivalis adherence to streptococci. Consistent with this, the KKVQDLLKK and NITVK motifs are conserved only in antigen I/II proteins expressed by the oralis group of streptococci, which interact with P. gingivalis. Interestingly, the primary and secondary structures and the functional characteristics of the amphipathic VQDLL core {alpha}-helix resemble the consensus nuclear receptor (NR) box protein-protein interacting domain sequence (LXXLL) of eukaryotes. BAR peptides containing amino acid substitutions with the potential to disrupt the secondary structure of VQDLL were less-effective inhibitors of P. gingivalis adherence and biofilm formation, suggesting that the {alpha}-helical character of VQDLL is important. Furthermore, replacing the lysines that flank VQDLL with acidic amino acids also reduced inhibitory activity, suggesting that the association of VQDLL with Mfa1 may be stabilized by a charge clamp. These results indicate that the Mfa1-interacting interface of streptococcal antigen I/II encompasses both the KKVQDLLKK and NITVK motif and suggest that the adherence of P. gingivalis to streptococci is driven by a protein-protein interaction domain that resembles the eukaryotic NR box. Thus, both motifs must be taken into account in designing potential peptidomimetics that target P. gingivalis adherence and biofilm formation.

* Corresponding author. Mailing address: Department of Periodontics, Endodontics, and Dental Hygiene, University of Louisville School of Dentistry, 501 South Preston Street, Room 209, Louisville, KY 40292. Phone: (502) 852-3807. Fax: (502) 852-4052. E-mail: drdemu01{at}louisville.edu

{triangledown} Published ahead of print on 12 May 2008.

Editor: A. Camilli

Infection and Immunity, July 2008, p. 3273-3280, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00366-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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