Abstract
The mannose receptor of macrophages and liver endothelium mediates clearance of pathogenic organisms and potentially harmful glycoconjugates. The extracellular portion of the receptor includes eight C-type carbohydrate recognition domains (CRDs), of which one, CRD-4, shows detectable binding to monosaccharide ligands. We have determined the crystal structure of CRD-4. Although the basic C-type lectin fold is preserved, a loop extends away from the core of the domain to form a domain-swapped dimer in the crystal. Of the two Ca(2+) sites, only the principal site known to mediate carbohydrate binding in other C-type lectins is occupied. This site is altered in a way that makes sugar binding impossible in the mode observed in other C-type lectins. The structure is likely to represent an endosomal form of the domain formed when Ca(2+) is lost from the auxiliary calcium site. The structure suggests a mechanism for endosomal ligand release in which the auxiliary calcium site serves as a pH sensor. Acid pH-induced removal of this Ca(2+) results in conformational rearrangements of the receptor, rendering it unable to bind carbohydrate ligands.
Highlights
The mannose receptor of macrophages and liver endothelial cells acts as a molecular scavenger, binding to and internalizing a variety of pathogenic microorganisms and potentially harmful glycoproteins (1, 2)
This paper describes structural analysis of carbohydrate recognition domains (CRDs)-4 of the mannose receptor by crystallography
Overall Structure of Mannose Receptor CRD-4 and Comparison to Other C-type Lectins—The structure of mannose receptor CRD-4 was determined by molecular replacement using a search model composed of three superimposed C-type CRDs
Summary
The mannose receptor of macrophages and liver endothelial cells acts as a molecular scavenger, binding to and internalizing a variety of pathogenic microorganisms and potentially harmful glycoproteins (1, 2). Ca2ϩ site 2 of MBPs, which is conserved among all C-type lectin-like domains with sugar binding activity and participates in direct interactions with bound sugar ligands, is formed in part by residues from extended loops as well as residues from 4.
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