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Critical role of the solvent environment in galectin-1 binding to the disaccharide lactose.

ABSTRACT: Galectin-1 (Gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, binds specifically to poly-N-acetyllactosamine-enriched glycoconjugates. Through interactions with these glycoconjugates, this protein modulates inflammatory responses and contributes to tumor progression and immune cell homeostasis. The carbohydrate recognition domain includes the single protein tryptophan (Trp68). UV resonance Raman spectroscopy and molecular dynamic simulation were used to examine the change in the environment of the Trp on ligand binding. The UV Raman spectra and the calculated water radial distribution functions show that, while no large structural changes in the protein follow lactose binding, substantial solvent reorganization occurs. These new insights into the microscopic role of water molecules in Gal-1 binding to its specific carbohydrate ligands provides a better understanding of the physicochemical properties of Gal-1-saccharide interactions, which will be useful for the design of synthetic inhibitors for therapeutic purposes.

SUBMITTER: Di Lella S

PROVIDER: S-EPMC2633424 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Critical role of the solvent environment in galectin-1 binding to the disaccharide lactose.

Di Lella Santiago S Ma Lu L Ricci Juan C Díaz JC Rabinovich Gabriel A GA Asher Sanford A SA Alvarez R María S RM

Biochemistry 20090201 4

Galectin-1 (Gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, binds specifically to poly-N-acetyllactosamine-enriched glycoconjugates. Through interactions with these glycoconjugates, this protein modulates inflammatory responses and contributes to tumor progression and immune cell homeostasis. The carbohydrate recognition domain includes the single protein tryptophan (Trp68). UV resonance Raman spectroscopy and molecular dynamic simulation were used to examine th ...[more]

PMID: 19128029

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Project description:BackgroundLactose synthesis rate is an important factor in milk production and quality in mammals. Understanding the lactose synthesis mechanism is crucial for the improvement of milk quantity and quality. However, research on the temporal gene changes regarding lactose synthesis during the whole lactation is still limited. The objective of this study was to determine gene expression profiles related to lactose synthesis in sows during lactation, and further identify the critical steps or key factors in the lactose synthesis pathway.MethodsTo determine the temporal change of factors related to lactose synthesis in sows, milk from eight multiparous Yorkshire sows (parity 3 to 6) was collected at 0 h, 2 h, 6 h, 12 h, 24 h, day 2, 3, 4, 7, 14, and 21 after birth of the first piglet. Lactose content, prolactin and progesterone concentration, and gene or protein expression related to lactose synthesis were measured.ResultsThe lactose yield increased gradually from D2 to D21 and reached a maximum at D14 (3-fold from D2) during lactation (P < 0.05). A similar trend was observed in IGF-1 and insulin concentrations in milk, both of which were greatest at D3 with a subsequent decrease during middle to late lactation. Conversely, milk prolactin and progesterone concentrations moderately decreased with the progression of lactation. The mRNA or protein expressions related to glucose transportation (GLUT1), glucose-galactose interconversion (HK1 and UGP2), UDP-galactose transportation (SLC35A2), and lactose synthetase (LALBA and B4GALT1) in the lactose synthesis pathway were significantly upregulated during early to middle lactation and plateaued by late lactation (P < 0.05).ConclusionsThese novel findings suggest that the increased lactose synthesis in lactation was related to the coordinated upregulation of genes or enzymes in the lactose synthesis pathway, and glucose transportation (GLUT1) and lactose synthetase (LALBA and B4GALT1) might be the critical steps in the lactose synthesis pathway of sows during lactation.

Project description:Background: In several types of malignancies, especially EBV-associated nasopharyngeal carcinomas, high Galectin-9 (Gal-9) expression is indicative of an aggressive tumor phenotype. The contribution of Gal-9 to the oncogenesis of B-cell lymphomas (BCLs) has not yet been investigated. Methods: The expression of Gal-9, STING, and EBNA1 was measured by immunohistochemical (IHC) staining on tumor sections from 66 BCL patients. Artificial EBV infection of normal primary B cells in vitro was used as an experimental model. The dynamic changes of the transcriptome of EBV-infected B cells undergoing transformation were investigated by bulk RNA-sequencing and bioinformatics analysis. The oncogenic role of Gal-9 was investigated in vitro by addition of recombinant Gal-9 to EBV-infected primary B-cells, and growth assays. The underlying molecular mechanisms were investigated by immunoblotting and immunofluorescent (IF) staining, CHIP and luciferase reporter assays. Results: In clinical specimens of BCLs, Gal-9 expression was significantly associated with tumor stage, latent EBV infection and abundance of the viral latent protein EBNA1. Looking at the transcriptome changes occurring in vitro during EBV-driven B-cell transformation, we could identify a series of genes undergoing long term activation and remaining highly expressed in mature LCLs. The Gal-9 gene is one of them. Its expression is enhanced during the transformation process at the mRNA level and even more at the protein level. This up-regulation results at least in part from its transactivation by EBNA1 which can bind its promoter. Reciprocally, we find that addition of extra-cellular Gal-9 promotes B-cell transformation and establishment of the latent phase of EBV-infection. Concomitantly, extra-cellular Gal-9 blocks STING signaling and enhances STAT3 phosphorylation. Inhibition of Sting signaling or STAT3 phosphorylation blocks B-cell transformation, even in the presence of Gal-9. Conclusion: our data unveil a role of amplification and acceleration for Gal-9 in the process of EBV-driven B-cell transformation. This process might be relevant to the pathogenesis of EBV-associated BCLs.

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Critical role of the solvent environment in galectin-1 binding to the disaccharide lactose.

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Critical role of the solvent environment in galectin-1 binding to the disaccharide lactose.

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