title: Structural insights into SraP-mediated Staphylococcus aureus adhesion to host cells.
abstract: Staphylococcus aureus, a Gram-positive bacterium causes a number of devastating human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis. S. aureus SraP, a surface-exposed serine-rich repeat glycoprotein (SRRP), is required for the pathogenesis of human infective endocarditis via its ligand-binding region (BR) adhering to human platelets. It remains unclear how SraP interacts with human host. Here we report the 2.05 Å crystal structure of the BR of SraP, revealing an extended rod-like architecture of four discrete modules. The N-terminal legume lectin-like module specifically binds to N-acetylneuraminic acid. The second module adopts a β-grasp fold similar to Ig-binding proteins, whereas the last two tandem repetitive modules resemble eukaryotic cadherins but differ in calcium coordination pattern. Under the conditions tested, small-angle X-ray scattering and molecular dynamic simulation indicated that the three C-terminal modules function as a relatively rigid stem to extend the N-terminal lectin module outwards. Structure-guided mutagenesis analyses, in addition to a recently identified trisaccharide ligand of SraP, enabled us to elucidate that SraP binding to sialylated receptors promotes S. aureus adhesion to and invasion into host epithelial cells. Our findings have thus provided novel structural and functional insights into the SraP-mediated host-pathogen interaction of S. aureus.
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Yi-Hu
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Jiang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Bai
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Yan-Min
authors.initials: YM
authors.lastname: Ren
authors.affiliation: Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Yide
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xue
authors.affiliation: Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, People's Republic of China.
authors.forename: Jing-Ren
authors.initials: JR
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei Anhui, People's Republic of China.
authors.forename: Cong-Zhao
authors.initials: CZ
authors.lastname: Zhou
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001422:Bacterial Adhesion; D001665:Binding Sites; D002460:Cell Line; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D019158:N-Acetylneuraminic Acid / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000472:pathogenicity / Q000502:physiology*; D014312:Trisaccharides / Q000737:chemistry / Q000378:metabolism; D037521:Virulence Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D008024:Ligands; D050505:Mutant Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014312:Trisaccharides; D037521:Virulence Factors; C048165:adhesin, Staphylococcus aureus; D049452:Green Fluorescent Proteins; D019158:N-Acetylneuraminic Acid