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Title: Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle

Journal Article · · Journal of Biological Chemistry
 [1];  [2];  [2];  [3];  [3];  [3];  [1];  [2];  [2]
  1. Stanford Univ. School of Medicine, CA (United States)
  2. Imperial College, London (United Kingdom)
  3. Aarhus Univ. (Denmark)
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The macrophage receptor mincle binds to trehalose dimycolate on the surface of Mycobacterium tuberculosis. Signaling initiated by this interaction leads to cytokine production, which underlies the ability of mycobacteria to evade the immune system and also to function as adjuvants. In previous work the mechanism for binding of the sugar headgroup of trehalose dimycolate to mincle has been elucidated, but the basis for enhanced binding to glycolipid ligands, in which hydrophobic substituents are attached to the 6-hydroxyl groups, has been the subject of speculation. In the work reported here, the interaction of trehalose derivatives with bovine mincle has been probed with a series of synthetic mimics of trehalose dimycolate in binding assays, in structural studies by x-ray crystallography, and by site-directed mutagenesis. Binding studies reveal that, rather than reflecting specific structural preference, the apparent affinity of mincle for ligands with hydrophobic substituents correlates with their overall size. Structural and mutagenesis analysis provides evidence for interaction of the hydrophobic substituents with multiple different portions of the surface of mincle and confirms the presence of three Ca2+-binding sites. The structure of an extended portion of the extracellular domain of mincle, beyond the minimal C-type carbohydrate recognition domain, also constrains the way the binding domains may interact on the surface of macrophages.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
Biotechnology and Biological Sciences Research Council; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; AC02-76SF00515
OSTI ID:
1357638
Journal Information:
Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 40 Vol. 291; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (13)

Mincle: 20 years of a versatile sensor of insults journal May 2018
Interaction of Glycolipids with the Macrophage Surface Receptor Mincle – a Systematic Molecular Dynamics Study journal March 2018
Host Responses to Malassezia spp. in the Mammalian Skin text January 2017
ortho -Substituted lipidated Brartemicin derivative shows promising Mincle-mediated adjuvant activity journal January 2020
Synthesis of glycerolipids containing simple linear acyl chains or aromatic rings and evaluation of their Mincle signaling activity journal January 2019
Rational design of adjuvants targeting the C-type lectin Mincle journal February 2017
Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity journal April 2017
Sensing Lipids with Mincle: Structure and Function journal November 2017
Macrophage Inducible C-Type Lectin As a Multifunctional Player in Immunity journal July 2017
Host Responses to Malassezia spp. in the Mammalian Skin journal November 2017
Mammalian sugar‐binding receptors: known functions and unexplored roles journal February 2019
Contact, Collaboration, and Conflict: Signal Integration of Syk-Coupled C-Type Lectin Receptors journal February 2017
Draft Genome Sequence of Nonomuraea sp. Strain C10, a Producer of Brartemicin, Isolated from a Mud Dauber Wasp Nest in Nepal journal November 2019

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
carbohydrate-binding protein
glycolipid
lectin
mycobacteria
tuberculosis