Common polymorphisms in human langerin change specificity for glycan ligands
Hadar Feinberg1, Thomas J W Rowntree, Shawn L W Tan
1From the Department of Life Sciences, Imperial College, London SW7 2AZ, United Kingdom and.
The Journal of Biological Chemistry
|November 13, 2013
Summary
Single nucleotide polymorphisms (SNPs) in human langerin alter its carbohydrate binding. The K313I variant abolishes 6SO4-Gal binding and enhances GlcNAc binding, potentially impacting pathogen susceptibility.
Area of Science:
- Immunology
- Glycobiology
- Structural Biology
Background:
- Langerin, a C-type lectin on Langerhans cells, is crucial for pathogen uptake and antigen presentation.
- It recognizes diverse carbohydrate structures, including sulfated glycans.
Purpose of the Study:
- To investigate the functional impact of common single nucleotide polymorphisms (SNPs) in human langerin on its glycan-binding properties.
- To understand how specific amino acid changes affect ligand recognition and affinity.
Main Methods:
- Site-directed mutagenesis to create specific langerin variants.
- Quantitative binding assays and glycan array screening to assess carbohydrate interactions.
- Structural analysis to elucidate molecular mechanisms of binding changes.
Main Results:
- The Lys-313 to Isoleucine (K313I) polymorphism abolishes binding to terminal 6-sulfated galactose (6SO4-Gal) glycans.
- This variant enhances binding to N-acetylglucosamine (GlcNAc)-terminated glycans, potentially due to Ile-313 interaction.
- A linked N288D polymorphism reduces overall glycan affinity by destabilizing the calcium-binding site.
- The combined N288D and K313I polymorphisms result in altered langerin function with no 6SO4-Gal binding and increased GlcNAc binding.
Conclusions:
- Common langerin polymorphisms significantly alter carbohydrate specificity and binding affinity.
- These functional changes in langerin may influence susceptibility to microbial infections.
- Understanding these variants is key to comprehending immune responses to pathogens.
Related Concept Videos
01:05Proteoglycans
4.1K
Glycans, a class of complex heterogeneous molecules, can be covalently attached to proteins to form glycosylated proteins that regulate various physiological and pathological processes. Glycosylated proteins or glycoproteins comprise N-linked and O-linked oligosaccharides. O-glycosylation is the most common type of protein glycosylation. Here, glycans attach to the oxygen atom of the hydroxyl groups of Serine or Threonine residues. O-linked glycosylation occurs later in protein processing,...
4.1K
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
160
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
160
00:49Ligand Binding and Linkage
4.4K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.4K
01:16Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
189
The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
189
01:25Selectins
3.6K
Cell adhesion is an essential aspect of multicellularity. While stable cell interactions usually occur between cells of the same type, transient cell interactions occur between cells of different tissue types, such as between neutrophils and endothelial cells. Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands to form transient cell adhesion. They are rod-like proteins with a long extracellular part of variable length ending with the lectin domain,...
3.6K
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
84
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
84