Three-Dimensional Structures of Galectins

Kamitori, Shigehiro

doi:10.4052/tigg.1731.1se

Cited by 24 publications

(13 citation statements)

References 18 publications

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“…Structurally, all galectins share a highly conserved β‐sandwich fold consisting of a six‐stranded β‐sheet on one face (S‐face or sugar‐binding face) and a five‐stranded β‐sheet on the opposing face (F‐face) . Gal‐3 is unique among galectins, because it has a relatively long N‐terminal tail (NT) extending out from its CRD.…”

Section: Introductionmentioning

confidence: 99%

Chemokines and galectins form heterodimers to modulate inflammation

Eckardt¹,

Miller

Blanchet³

et al. 2020

EMBO Reports

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Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.

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Section: Introductionmentioning

confidence: 99%

Chemokines and galectins form heterodimers to modulate inflammation

Eckardt¹,

Miller

Blanchet³

et al. 2020

EMBO Reports

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“…Galectins play crucial roles in adaptive and innate immunity, inflammation, apoptosis, and cancer [2][3][4][5]. Human galectins are classified into three types based on their global structures [6][7][8][9][10]. Gal-3 is the only member of chimera-type galectin with a long N-terminal tail and a C-terminal carbohydrate recognition domain (CRD) [11].…”

Section: Introductionmentioning

confidence: 99%

Structure–function studies of galectin‐14, an important effector molecule in embryology

Yang

et al. 2020

The FEBS Journal

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The expression of prototype galectin‐14 (Gal‐14) in human placenta is higher than any other galectin, suggesting that it may play a role in fetal development and regulation of immune tolerance during pregnancy. Here, we solved the crystal structure of dimeric Gal‐14 and found that its global fold is significantly different from that of other galectins with two β‐strands (S5 and S6) extending from one monomer and contributing to the carbohydrate‐binding domain of the other. The hemagglutination assay showed that this lectin could induce agglutination of chicken erythrocytes, even though lactose could not inhibit Gal‐14‐induced agglutination activity. Calorimetry indicates that lactose does not interact with this lectin. Compared to galectin‐1, galectin‐3, and galectin‐8, Gal‐14 has two key amino acids (a histidine and an arginine) in the normally conserved, canonical sugar‐binding site, which are substituted by glutamine (Gln53) and histidine (His57), thus likely explaining why lactose binding to this lectin is very weak. Lactose was observed in the ligand‐binding site of one Gal‐14 structure, most likely because ligand binding is weak and crystals were allowed to grow over a long period of time in the presence of lactose. We also found that EGFP‐tagged Gal‐14 is primarily localized within the nucleus of different cell types. In addition, Gal‐14 colocalized with c‐Rel (a member of NF‐κB family) in HeLa cells. These findings indicate that Gal‐14 might regulate signal transduction pathways through NF‐κB hubs. Overall, the present study provides impetus for further research into the function of Gal‐14 in embryology.

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“…In addition to affecting interactions with protein counter-receptors and relative positions of members of the cysteine pair, this region around P4 at the interface could also regulate the extent of hetero-dimerization with subunits of other galectins, such as Gal-1 or -3, documented to occur recently [83]. When looking at galectin structures [84], crystallographic evidence for an isomerization at this site to the cis-state is available for the Charcot-Leyden crystal protein [85] (termed Gal-10) despite a lack to bind the canonical glycan ligand lactose as is the case for the galectin-related protein [6,86]. The conservation of proline within the N-terminal stretch (albeit to a limited extent) and the difference with the analogous pair CG-1A/B (CG-1A and also human Gal-1 having a leucine rather than proline at the equivalent position) hypothetically indicate a possible relevance, thus warranting investigation with functional studies.…”

Section: Discussionmentioning

confidence: 99%

Pro4 prolyl peptide bond isomerization in human galectin-7 modulates the monomer-dimer equilibrum to affect function

Miller

Nesmelova

Daragan

et al. 2020

Biochemical Journal

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Human galectin-7 (Gal-7; also termed p53-induced gene 1 product) acts as a multifunctional effector by productive pairing with distinct glycoconjugates and protein counter-receptors in the cytoplasm and nucleus, as well as on the cell surface. Its structural analysis by NMR spectroscopy detected doubling of a set of particular resonances, an indicator of Gal-7 existing in two conformational states in slow exchange on the chemical shift time scale. Structural positioning of this set of amino acids around the P4 residue and loss of this phenomenon in the bioactive P4L mutant indicated cis-trans isomerization at this site. Respective resonance assignments confirmed our proposal of two Gal-7 conformers. Mapping hydrogen bonds and considering van der Waals interactions in molecular dynamics simulations revealed a structural difference for the N-terminal peptide, with the trans-state being more exposed to solvent and more mobile than the cis-state. Affinity for lactose or glycan-inhibitable neuroblastoma cell surface contact formation was not affected, because both conformers associated with an overall increase in order parameters (S2). At low µM concentrations, homodimer dissociation is more favored for the cis-state of the protein than its trans-state. These findings give direction to mapping binding sites for protein counter-receptors of Gal-7, such as Bcl-2, JNK1, p53 or Smad3, and to run functional assays at low concentration to test the hypothesis that this isomerization process provides a (patho)physiologically important molecular switch for Gal-7.

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Three-Dimensional Structures of Galectins

Cited by 24 publications

References 18 publications

Chemokines and galectins form heterodimers to modulate inflammation

Chemokines and galectins form heterodimers to modulate inflammation

Structure–function studies of galectin‐14, an important effector molecule in embryology

Pro4 prolyl peptide bond isomerization in human galectin-7 modulates the monomer-dimer equilibrum to affect function

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