Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL

Area of Science:

• Immunology
• Structural Biology
• Glycobiology

Background:

• Mincle (macrophage inducible Ca(2+)-dependent C-type lectin; CLEC4E) and MCL (macrophage C-type lectin; CLEC4D) are key receptors for mycobacterial glycolipids.
• These receptors bind trehalose-6,6'-dimycolate (TDM), a component of mycobacterial cell surfaces, activating immune cells and providing adjuvant activity.

Purpose of the Study:

• To elucidate the molecular mechanisms by which Mincle and MCL recognize glycolipids.
• To understand the structural basis of TDM recognition by these C-type lectin receptors.

Main Methods:

• Determined crystal structures of Mincle, MCL, and a Mincle-citric acid complex.
• Conducted functional studies using mutant receptors and glycolipid ligands.

Main Results:

• Revealed Ca(2+)-dependent sugar binding by Mincle and MCL, consistent with other C-type lectins.
• Identified unique shallow hydrophobic regions adjacent to sugar-binding sites in Mincle and MCL, crucial for recognizing glycolipid fatty acid moieties.
• Functional studies validated the proposed glycolipid binding mode.

Conclusions:

• Mincle and MCL recognize TDM through a combination of sugar binding and hydrophobic interactions with fatty acids.
• The findings provide molecular insights into glycolipid recognition by C-type lectin receptors.
• This understanding may guide the rational design of novel and effective immune adjuvants.