biostudies-literatureUnknownMills KBNIAID NIH HHSNIGMS NIH HHSNIH HHS<i>Staphylococcus aureus</i> causes the majority of skin and soft tissue infections, but this pathogen only transiently colonizes healthy skin. However, this transient skin exposure enables <i>S. aureus</i> to transition to infection. Initial adhesion of <i>S. aureus</i> to skin corneocytes is mediated by surface protein G (SasG). Here, phylogenetic analyses reveal the presence of two major divergent SasG alleles in <i>S. aureus</i>, SasG-I and SasG-II. Structural analyses of SasG-II identified a unique non-aromatic arginine in the binding pocket of the lectin subdomain that mediates adhesion to corneocytes. Atomic force microscopy and corneocyte adhesion assays indicated SasG-II can bind to a broader variety of ligands than SasG-I. Glycosidase treatment resulted in different binding profiles between SasG-I and SasG-II on skin cells. Additionally, SasG-mediated adhesion was recapitulated using differentiated N/TERT keratinocytes. Our findings indicate that SasG-II has evolved to adhere to multiple ligands, conferring a distinct advantage to <i>S. aureus</i> during skin colonization.bioRxiv : the preprint server for biology2023.11.20.567970https://www.ebi.ac.uk/biostudies/studies/S-EPMC10690190biostudies-literature<i>Staphylococcus aureus</i> skin colonization is mediated by SasG lectin variation.PMC10690190R56 AI162964R01 GM094363P30 GM124165S10 OD021527R01 AI162964Fey PDHerr ABMaciag JJDufrene YFCrawford JARobinson DAWang CHorswill AREnroth TJMills KBKeim KCfalse<i>Staphylococcus aureus</i> skin colonization is mediated by SasG lectin variation.<i>Staphylococcus aureus</i> causes the majority of skin and soft tissue infections, but this pathogen only transiently colonizes healthy skin. However, this transient skin exposure enables <i>S. aureus</i> to transition to infection. Initial adhesion of <i>S. aureus</i> to skin corneocytes is mediated by surface protein G (SasG). Here, phylogenetic analyses reveal the presence of two major divergent SasG alleles in <i>S. aureus</i>, SasG-I and SasG-II. Structural analyses of SasG-II identified a unique non-aromatic arginine in the binding pocket of the lectin subdomain that mediates adhesion to corneocytes. Atomic force microscopy and corneocyte adhesion assays indicated SasG-II can bind to a broader variety of ligands than SasG-I. Glycosidase treatment resulted in different binding profiles between SasG-I and SasG-II on skin cells. Additionally, SasG-mediated adhesion was recapitulated using differentiated N/TERT keratinocytes. Our findings indicate that SasG-II has evolved to adhere to multiple ligands, conferring a distinct advantage to <i>S. aureus</i> during skin colonization.2023-01-01T00:00:00Z2023 Nov2025-09-01T03:16:44.627Z2025-04-25T17:22:59.518ZS-EPMC106901903804527510.1101/2023.11.20.567970