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J Biol Chem. 2013 Oct 4;288(40):28457-65. doi: 10.1074/jbc.M113.497149. Epub 2013 Aug 19.

Mechanism for recognition of an unusual mycobacterial glycolipid by the macrophage receptor mincle.

Author information

1
From the Departments of Structural Biology and Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 and.

Abstract

Binding of the macrophage lectin mincle to trehalose dimycolate, a key glycolipid virulence factor on the surface of Mycobacterium tuberculosis and Mycobacterium bovis, initiates responses that can lead both to toxicity and to protection of these pathogens from destruction. Crystallographic structural analysis, site-directed mutagenesis, and binding studies with glycolipid mimics have been used to define an extended binding site in the C-type carbohydrate recognition domain (CRD) of bovine mincle that encompasses both the headgroup and a portion of the attached acyl chains. One glucose residue of the trehalose Glcα1-1Glcα headgroup is liganded to a Ca(2+) in a manner common to many C-type CRDs, whereas the second glucose residue is accommodated in a novel secondary binding site. The additional contacts in the secondary site lead to a 36-fold higher affinity for trehalose compared with glucose. An adjacent hydrophobic groove, not seen in other C-type CRDs, provides a docking site for one of the acyl chains attached to the trehalose, which can be targeted with small molecule analogs of trehalose dimycolate that bind with 52-fold higher affinity than trehalose. The data demonstrate how mincle bridges between the surfaces of the macrophage and the mycobacterium and suggest the possibility of disrupting this interaction. In addition, the results may provide a basis for design of adjuvants that mimic the ability of mycobacteria to stimulate a response to immunization that can be employed in vaccine development.

KEYWORDS:

CLEC4E; Carbohydrate-binding Protein; Cord Factor; Crystal Structure; Glycobiology; Glycolipids; Mycobacterium tuberculosis

PMID:
23960080
PMCID:
PMC3789947
DOI:
10.1074/jbc.M113.497149
[Indexed for MEDLINE]
Free PMC Article

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