title: Lipoprotein cofactors located in the outer membrane activate bacterial cell wall polymerases.
abstract: Most bacteria surround themselves with a peptidoglycan (PG) exoskeleton synthesized by polysaccharide polymerases called penicillin-binding proteins (PBPs). Because they are the targets of penicillin and related antibiotics, the structure and biochemical functions of the PBPs have been extensively studied. Despite this, we still know surprisingly little about how these enzymes build the PG layer in vivo. Here, we identify the Escherichia coli outer-membrane lipoproteins LpoA and LpoB as essential PBP cofactors. We show that LpoA and LpoB form specific trans-envelope complexes with their cognate PBP and are critical for PBP function in vivo. We further show that LpoB promotes PG synthesis by its partner PBP in vitro and that it likely does so by stimulating glycan chain polymerization. Overall, our results indicate that PBP accessory proteins play a central role in PG biogenesis, and like the PBPs they work with, these factors are attractive targets for antibiotic development.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Paradis-Bleau
authors.forename: Monica
authors.initials: M
authors.lastname: Markovski
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Uehara
authors.forename: Tania J
authors.initials: TJ
authors.lastname: Lupoli
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kahne
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Bernhardt
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D002473:Cell Wall / Q000201:enzymology* / Q000378:metabolism; D004926:Escherichia coli / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D010457:Peptidoglycan / Q000096:biosynthesis* / Q000378:metabolism; D046928:Peptidoglycan Glycosyltransferase / Q000378:metabolism; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D008074:Lipoproteins; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; D046928:Peptidoglycan Glycosyltransferase; C478681:penicillin-binding protein 1B, E coli; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase