title: Hijacking of a substrate-binding protein scaffold for use in mycobacterial cell wall biosynthesis.
abstract: The waxy cell wall is crucial to the survival of mycobacteria within the infected host. The cell wall is a complex structure rich in unusual molecules that includes two related lipoglycans, the phosphatidylinositol mannosides (PIMs) and lipoarabinomannans (LAMs). Many proteins implicated in the PIM/LAM biosynthetic pathway, while attractive therapeutic targets, are poorly defined. The 2.4A resolution crystal structure of an essential lipoprotein, LpqW, implicated in LAM biosynthesis is reported here. LpqW adopts a scaffold reminiscent of the distantly related, promiscuous substrate-binding proteins of the ATP-binding cassette import system. Nevertheless, the unique closed conformation of LpqW suggests that mycobacteria and other closely related pathogens have hijacked this scaffold for use in key processes of cell wall biosynthesis. In silico docking provided a plausible model in which the candidate PIM ligand binds within a marked electronegative region located on the surface of LpqW. We suggest that LpqW represents an archetypal lipoprotein that channels intermediates from a pathway for mature PIM production into a pathway for LAM biosynthesis, thus controlling the relative abundance of these two important components of the cell wall.
authors.affiliation: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Vic. 3800, Australia.
authors.forename: Zara
authors.initials: Z
authors.lastname: Marland
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: Leyla
authors.initials: L
authors.lastname: Zaker-Tabrizi
authors.forename: Isabelle S
authors.initials: IS
authors.lastname: Lucet
authors.forename: Rajini
authors.initials: R
authors.lastname: Brammananth
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.forename: Matthew C J
authors.initials: MC
authors.lastname: Wilce
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crellin
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008070:Lipopolysaccharides / Q000096:biosynthesis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000378:metabolism; D010802:Phylogeny; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
chemical_list: D001426:Bacterial Proteins; D008070:Lipopolysaccharides; C510627:LpqW protein, Mycobacterium tuberculosis; D010716:Phosphatidylinositols; C050016:lipoarabinomannan; C034154:phosphatidylinositol mannoside