Dataset Information

Structural aspects of binding of ?-linked digalactosides to human galectin-1.

ABSTRACT: By definition, adhesion/growth-regulatory galectins are known for their ability to bind ?-galactosides such as Gal?(1 ? 4)Glc (lactose). Indications for affinity of human galectin-1 to ?-linked digalactosides pose questions on the interaction profile with such bound ligands and selection of the galactose moiety for CH-? stacking. These issues are resolved by a combination of (15)N-(1)H heteronuclear single quantum coherence (HSQC) chemical shift and saturation transfer difference nuclear magnetic resonance (STD NMR) epitope mappings with docking analysis, using the ?(1 ? 3/4)-linked digalactosides and also Gal?(1 ? 6)Glc (melibiose) as test compounds. The experimental part revealed interaction with the canonical lectin site, and this preferentially via the non-reducing-end galactose moiety. Low-energy conformers appear to be selected without notable distortion, as shown by molecular dynamics simulations. With the ?(1 ? 4) disaccharide, however, the typical CH-? interaction is significantly diminished, yet binding appears to be partially compensated for by hydrogen bonding. Overall, these findings reveal that the type of ?-linkage in digalactosides has an impact on maintaining CH-? interactions and the pattern of hydrogen bonding, explaining preference for the ?(1 ? 3) linkage. Thus, this lectin is able to accommodate both ?- and ?-linked galactosides at the same site, with major contacts to the non-reducing-end sugar unit.

SUBMITTER: Miller MC

PROVIDER: S-EPMC3219418 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Publications

Structural aspects of binding of α-linked digalactosides to human galectin-1.

Miller Michelle C MC Ribeiro João P JP Roldós Virginia V Martín-Santamaría Sonsoles S Cañada F Javier FJ Nesmelova Irina A IA André Sabine S Pang Mabel M Klyosov Anatole A AA Baum Linda G LG Jiménez-Barbero Jesús J Gabius Hans-Joachim HJ Mayo Kevin H KH

Glycobiology 20110628 12

By definition, adhesion/growth-regulatory galectins are known for their ability to bind β-galactosides such as Galβ(1 → 4)Glc (lactose). Indications for affinity of human galectin-1 to α-linked digalactosides pose questions on the interaction profile with such bound ligands and selection of the galactose moiety for CH-π stacking. These issues are resolved by a combination of (15)N-(1)H heteronuclear single quantum coherence (HSQC) chemical shift and saturation transfer difference nuclear magneti ...[more]

PMID: 21712397

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Project description:The concept of biomedical significance of the functional pairing between tissue lectins and their glycoconjugate counterreceptors has reached the mainstream of research on the flow of biological information. A major challenge now is to identify the principles of structure-activity relationships that underlie specificity of recognition and the ensuing post-binding processes. Toward this end, we focus on a distinct feature on the side of the lectin, i.e. its architecture to present the carbohydrate recognition domain (CRD). Working with a multifunctional human lectin, i.e. galectin-3, as model, its CRD is used in protein engineering to build variants with different modular assembly. Hereby, it becomes possible to compare activity features of the natural design, i.e. CRD attached to an N-terminal tail, with those of homo- and heterodimers and the tail-free protein. Thermodynamics of binding disaccharides proved full activity of all proteins at very similar affinity. The following glycan array testing revealed maintained preferential contact formation with N-acetyllactosamine oligomers and histo-blood group ABH epitopes irrespective of variant design. The study of carbohydrate-inhibitable binding of the test panel disclosed up to qualitative cell-type-dependent differences in sections of fixed murine epididymis and especially jejunum. By probing topological aspects of binding, the susceptibility to inhibition by a tetravalent glycocluster was markedly different for the wild-type vs the homodimeric variant proteins. The results teach the salient lesson that protein design matters: the type of CRD presentation can have a profound bearing on whether basically suited oligosaccharides, which for example tested positively in an array, will become binding partners in situ. When lectin-glycoconjugate aggregates (lattices) are formed, their structural organization will depend on this parameter. Further testing (ga)lectin variants will thus be instrumental (i) to define the full range of impact of altering protein assembly and (ii) to explain why certain types of design have been favored during the course of evolution, besides opening biomedical perspectives for potential applications of the novel galectin forms.

Dataset Information

Structural aspects of binding of ?-linked digalactosides to human galectin-1.

Publications

Structural aspects of binding of α-linked digalactosides to human galectin-1.

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