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Glycolipid recognition and binding by Siglec-6 hinges on interactions with the cell membrane
Silvia D'Andrea1, Edward N Schmidt2, Duong Bui2
1Department of Chemistry, Maynooth University, Maynooth, Ireland.
Communications Biology
|January 28, 2026
Summary
Siglec-6 partially uses a conserved Arg residue for binding gangliosides, supplementing energy via membrane phospholipid interactions. This reveals Siglec-6
Area of Science:
- Immunology
- Structural Biology
- Glycobiology
Background:
- Sialic acid-binding immunoglobulin-type lectins (Siglecs) are key regulators of immune responses.
- Human Siglecs utilize a conserved Arg residue for sialic acid binding, but exceptions exist.
- Siglec-6, MAG, and Siglec-11 may employ alternative binding mechanisms.
Purpose of the Study:
- To investigate the binding mechanism of Siglec-6 to monosialylated gangliosides.
- To elucidate the structural, mechanistic, and energetic details of this interaction.
- To understand the role of the conserved Arg residue and surrounding membrane environment.
Main Methods:
- All-atom molecular dynamics (MD) simulations.
- Binding assays.
- Mutagenesis studies.
Main Results:
- Siglec-6 partially relies on Arg122 for ganglioside recognition.
- Siglec-6 enhances binding energy through interactions with membrane phospholipids.
- Mutagenesis of Lys126 and Trp127 abrogates membrane interaction and binding.
Conclusions:
- Siglec-6 binding to gangliosides is a hybrid mechanism involving both canonical and non-canonical interactions.
- Membrane phospholipid interactions significantly contribute to Siglec-6 binding affinity.
- Siglec-6's adaptability illustrates how Siglecs diversify to bind specific sialosides within their biological context.
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