Diversity in recognition of glycans by F-type lectins and galectins: molecular, structural, and biophysical aspects

Abstract

Although lectins are "hard-wired" in the germline, the presence of tandemly arrayed carbohydrate recognition domains (CRDs), of chimeric structures displaying distinct CRDs, of polymorphic genes resulting in multiple isoforms, and in some cases, of a considerable recognition plasticity of their carbohydrate binding sites, significantly expand the lectin ligand-recognition spectrum and lectin functional diversification. Analysis of structural/functional aspects of galectins and F-lectins-the most recently identified lectin family characterized by a unique CRD sequence motif (a distinctive structural fold) and nominal specificity for l-Fuc-has led to a greater understanding of self/nonself recognition by proteins with tandemly arrayed CRDs. For lectins with a single CRD, however, recognition of self and nonself glycans can only be rationalized in terms of protein oligomerization and ligand clustering and presentation. Spatial and temporal changes in lectin expression, secretion, and local concentrations in extracellular microenvironments, as well as structural diversity and spatial display of their carbohydrate ligands on the host or microbial cell surface, are suggestive of a dynamic interplay of their recognition and effector functions in development and immunity.

Figure 1

Recognition and effector activities of the mannose-binding lectin (MBL). (A) The CRD recognizes equatorial hydroxyls on C3 and C4 of nonreducing terminal mannose with participation of the Ca²⁺ atom. (B) The MBL trimer binds to ligands that are displayed about 45 Å apart on the microbial surface, and via association with the MBL-associated serine protease (MASP) may activate the complement cascade, leading to opsonization or lysis of the microbe.

Figure 2

Structure and binding activities of F-type lectins. (A) Lateral view of the F-type lectins from the European eel(Anguilla anguilla agglutinin; AAA, left), a trimer of single-CRD subunits, and the striped bass (Morone saxatilis fucose-binding protein; MsFBP32, right) a trimer of binary CRD subunits. (B) Both AAA and MsFBP32-A binds to ligands that are displayed about 25Å apart (measure between fucose's O4) on the microbial or host cell surface. (C) AAA trimers can form oligomers and agglutinates cells; cross-linking of microbes and host phagocytic cells can lead to opsonization. MsFBP32 trimers have N-CRD and C-CRD clusters of distinct specificity. Binary CRD F-lectins have the capacity to crosslink microbes and phagocytes, and facilitate opsonization of bacteria.

Figure 3

Sequence variability in the loops surrounding the binding cleft of the eel agglutinin isoforms. (A) Sequence alignment of the AAA with eFL-1-7 isoforms showing variability in the loops CDR1 and CDR2. The amino acid replacements at several positions suggest a broader specificity for some isoforms, particularly eFL-1 and eFL-5. (B) Localization of the replacements and potential interactions are illustrated for CDR1 and CDR2. (C) The regions with highest sequence variability in the loops surrounding the binding cleft are illustrated with lighter blue and green color.

Figure 4

Structure and binding activities of galectins. (A) Structure of the galectin-1 dimer in complex with LacNAc. (B) Detail of the binding cleft indicating the amino acid residues that interact with the disaccharide. (C) Schematic illustration of cis-interactions of proto, chimera, and tandem repeat galectins with host cell surface glycans. (D) Schematic illustration of trans-interactions of proto, chimera, and tandem repeat galectins with host cell surface and microbial glycans. Proto and tandem repeat type galectins can cross-link host and microbial glycans. Chimera galectins (galectin-3) can recognize microbial glycans but it is not clear that they can cross-link them to the host cell surface.

Figure 5

Recognition of LacNAc and TDG by Bufo arenarum galectin-1. (A) Structure of the galectin-1 dimer in complex with LacNAc indicating the amino acid residues that interact with the disaccharides. (B) Structure of the galectin-1 in complex with TDG. (C) Overlap of the binding cleft.