R-type lectins
R-type lectins |
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Structure of the R-type CRD from the murine mannose receptor with bound 4-sulphated GalNAc
The sugar ligand is shown top right: black = carbon, red = oxygen, blue = nitrogen, yellow = sulphur. Protein Data Bank structure ID: 1DQ0.
Domain organization in proteins containing R-type lectin-like domains
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The R-type CRD is the only sugar-binding protein module from animal lectins that is also present in prokaryotes. The R-type CRD is named after the castor bean protein ricin, which is a member of a group of toxic soluble plant lectins. Ricin consists of an A subunit, which causes cytotoxicity by removing an essential ribosomal RNA base, thus inhibiting protein synthesis, and a B subunit, which binds terminal galactose residues on animal cell surface glycoproteins, initiating retrograde transport of the toxin through the secretory pathway. The B subunit consists of tandem R-type CRDs, and is produced with the A subunit as a single polypeptide precursor. The R-type CRD has a beta-trefoil structure, in which three lobes (designated alpha, beta and gamma), produced by an early gene duplication event, are arranged around a three-fold axis. At a ligand binding site, an aromatic residue stacks against the galactose ring, while hydrophilic residues from the same lobe make hydrogen bonds to the hydroxyl groups. A ligand binding site may be present in each lobe, enabling multiple interactions to be made with one glycan, but in many R-type CRDs only one or two lobes contain the essential conserved residues. Many bacterial hydrolases have an organization resembling that of the ricin precursor, with a hydrolase domain preceding an R-type CRD, the role of which is to anchor the catalytic domain to a polysaccharide substrate. In eukaryotes, many of the GalNAc transferase enzymes that initiate synthesis of O-linked oligosaccharides in the cis Golgi also have a related organization, with a transferase domain preceding an R-type CRD. The R-type CRDs in GalNAc transferases recognize previously synthesized O-linked glycans, leading to processive action of the transferase domain in the biosynthesis of densely O-glycosylated protein mucin-like regions. Proteins in the macrophage mannose receptor family also contain R-type CRDs, but have a very different architecture. These type I transmembrane proteins contain an N-terminal R-type CRD-like domain that is followed by a fibronectin type II domain and 8 or 10 C-type lectin-like domains. The R-type CRD in the mannose receptor interacts with 4-O-sulphated GalNAc residues on glycoprotein hormones such as lutrophin and thyrotrophin, leading to rapid clearance of these hormones from the circulation. The R-type CRD in the mannose receptor exhibits a different mechanism of ligand binding to the R-type CRDs in ricin and proteins of related architecture. 4-O-sulphated GalNAc is bound by a set of residues in the third lobe of the CRD, including an aromatic residue which stacks against the galactose ring, similarly to in the interaction between ricin and galactose, and residues which make hydrogen bonds to the sulphate moiety. The R-type domains in other members of the mannose receptor family lack the set of sugar-binding residues present in the mannose receptor.
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