Molecular and Structural Basis for Sugar Recognition by Mannose 6-Phosphate Receptor Homology Domain-Containing Lectins and Proteins

Abstract

N -Linked glycans play important roles in the determination of glycoprotein fates in cells through interactions with a variety of intracellular lectins. Most of the intracellular lectins possess carbohydrate recognition domain, which is homologous to legume lectins or mannose 6-phosphate receptors (MPRs). These lectins are categorized as L-type or P-type lectins. Besides L-type lectins, recently accumulated frontal affinity chromatography and glycan microarray data have demonstrated that P-type lectins and the MPR homology (MRH) domain-containing proteins have distinct sugar-binding specificity profiles. Furthermore, newly emerged three-dimensional structural data have revealed sugar recognition mechanisms at an atomic level. This review summarizes the current state of knowledge of molecular and structural basis for sugar recognition by P-type lectins and MRH domain-containing proteins that control folding, transport, and degradation of N-linked glycoproteins in the secretory pathway.

Lectins: Getting Familiar with Translators of the Sugar Code

“…The sequencing of lectin genes disclosed a functionally salient structural aspect beyond the contact site to the glycan: the lectin domain can be associated with other types of modules to establish a mosaic of active sites [ 50 , 51 ]. Membrane-spanning sections, regions for forming α-coiled coils or (non-)triple helical collagen-like repeats for oligomerization, immunoglobulin-like (or sushi) repeats as spacers or as sites for recognition of other types of ligand, even other types of CRDs (a β-trefoil domain in the tandem-repeat-type (C-type) mannose receptor active in “reading” the “postal code” for delivery (clearance) of pituitary glycoprotein hormones (please see Figure 2 b for epitope structure) or in lecticans binding hyaluronic acid), to list several examples, are encountered in this respect [ 52 , 53 , 54 , 55 , 56 ]. The structural organization in oligomers mentioned above is thus facilitated, as required for target specificity in the case of the just mentioned asialoglycoprotein receptor or of serum collectins [ 1 , 57 , 58 , 59 ].…”

Members of the Galectin Network with Deviations from the Canonical Sequence Signature. 2. <i>G</i>alectin-<i>R</i>elated <i>P</i>rotein (GRP)

“…Indeed, protein folds with sites to accommodate glycans occur frequently in Nature and have been delineated as versatile platforms for generating a wide variety of lectins (18)(19)(20)(21)(22)(23)(24). As their thorough analysis on the level of genes and crystal structures attests, an ancestral motif is the starting point for generating up to multiple homologous proteins during the course of evolution, a process establishing diversity in the families of lectins (18,23,(25)(26)(27)(28)(29)(30). Among them, the ga(lactose-binding)lectins that share the β-sandwich fold provide an instructive example for forming a network of β-galactosidespecific receptors (29,(31)(32)(33)(34)(35)(36).…”