Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2.
Knockout of lprG results in decreased virulence of Mycobacterium tuberculosis (MTB) in mice. MTB lipoprotein LprG has TLR2 agonist activity, which is thought to be dependent on its N-terminal triacylation. Unexpectedly, here we find that nonacylated LprG retains TLR2 activity. Moreover, we show LprG association with triacylated glycolipid TLR2 agonists lipoarabinomannan, lipomannan and phosphatidylinositol mannosides (which share core structures). Binding of triacylated species was specific to LprG (not LprA) and increased LprG TLR2 agonist activity; conversely, association of glycolipids with LprG enhanced their recognition by TLR2. The crystal structure of LprG in complex with phosphatidylinositol mannoside revealed a hydrophobic pocket that accommodates the three alkyl chains of the ligand. In conclusion, we demonstrate a glycolipid binding function of LprG that enhances recognition of triacylated MTB glycolipids by TLR2 and may affect glycolipid assembly or transport for bacterial cell wall biogenesis.
Drage
Michael G
MG
Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
Tsai
Han-Chun
HC
Pecora
Nicole D
ND
Cheng
Tan-Yun
TY
Arida
Ahmad R
AR
Shukla
Supriya
S
Rojas
Roxana E
RE
Seshadri
Chetan
C
Moody
D Branch
DB
Boom
W Henry
WH
Sacchettini
James C
JC
Harding
Clifford V
CV
D000215:Acylation; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006017:Glycolipids / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008074:Lipoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000378:metabolism
D001426:Bacterial Proteins; D006017:Glycolipids; D008070:Lipopolysaccharides; D008074:Lipoproteins; D010716:Phosphatidylinositols; D051195:Toll-Like Receptor 2; C050016:lipoarabinomannan; C064351:lipomannan; C034154:phosphatidylinositol mannoside