The group B streptococcal alpha C protein binds alpha1beta1-integrin through a novel KTD motif that promotes internalization of GBS within human epithelial cells.
Group B Streptococcus (GBS) is the leading cause of bacterial pneumonia, sepsis and meningitis among neonates and a cause of morbidity among pregnant women and immunocompromised adults. GBS epithelial cell invasion is associated with expression of alpha C protein (ACP). Loss of ACP expression results in a decrease in GBS internalization and translocation across human cervical epithelial cells (ME180). Soluble ACP and its 170 amino acid N-terminal region (NtACP), but not the repeat protein RR', bind to ME180 cells and reduce internalization of wild-type GBS to levels obtained with an ACP-deficient isogenic mutant. In the current study, ACP colocalized with alpha(1)beta(1)-integrin, resulting in integrin clustering as determined by laser scanning confocal microscopy. NtACP contains two structural domains, D1 and D2. D1 is structurally similar to fibronectin's integrin-binding region (FnIII10). D1's (KT)D146 motif is structurally similar to the FnIII10 (RG)D1495 integrin-binding motif, suggesting that ACP binds alpha(1)beta(1)-integrin via the D1 domain. The (KT)D146A mutation within soluble NtACP reduced its ability to bind alpha(1)beta(1)-integrin and inhibit GBS internalization within ME180 cells. Thus ACP binding to human epithelial cell integrins appears to contribute to GBS internalization within epithelial cells.
Department of Medicine, Brigham and Women's Hospital, 75 Fransis Street, Boston, MA 02115, USA.|Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA.
Gilles R
GR
Bolduc
Department of Medicine, Brigham and Women's Hospital, 75 Fransis Street, Boston, MA 02115, USA.|Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA.
Lawrence C
LC
Madoff
D020816:Amino Acid Motifs; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018988:Bacterial Translocation; D001665:Binding Sites; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology*; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism*; D018613:Microscopy, Confocal; D008958:Models, Molecular; D011485:Protein Binding; D013292:Streptococcus agalactiae / Q000472:pathogenicity*
D000954:Antigens, Surface; D001426:Bacterial Proteins; D039222:Integrin alpha1beta1; C077961:alpha C protein, group B streptococci