Non-synonymous single nucleotide polymorphisms in genes for immunoregulatory galectins: Association of galectin-8 (F19Y) occurrence with autoimmune diseases in a Caucasian population

Pál, Zsuzsanna; Antal, Péter; Srivastava, Sanjeev K.; Hullám, Gábor; Semsei, Ágnes F.; Gál, János; Svébis, Mihály; Soós, Györgyi; Szalai, Csaba; André, Sabine; Гордеева, Е. А.; Nagy, György; Kaltner, Herbert; Bovin, Nicolai V.; Molnár, Mária Judit; Falus, András; Gabius, Hans‐Joachim; Buzás, Edit I.

doi:10.1016/j.bbagen.2012.05.015

Cited by 27 publications

(22 citation statements)

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“…Because the linker is susceptible to proteolytic cleavage (20), the two CRDs can be separated from each other and present as free proteins. Equally interesting is the fact that Gal-8 is the first case of a single amino acid polymorphism in the coding region with medical relevance, i.e., associated with rheumatoid arthritis (21). The F19Y substitution causes a displacement of ∼1.5 Å of the positions of N-terminal amino acids 11-15 and a shift of the β-strand F0 in the vicinity of the linker, with impact on thermal stability and enthalpic/entropic contributions to ligand binding (22).…”

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confidence: 99%

Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface

Zhang

Moussodia

Vértesy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Surface-presented glycans (complex carbohydrates) are docking sites for adhesion/growth-regulatory galectins within cell-cell/ matrix interactions. Alteration of the linker length in human galectin-8 and single-site mutation (F19Y) are used herein to illustrate the potential of glycodendrimersomes with programmable glycan displays as a model system to reveal the functional impact of natural sequence variations in trans recognition. Extension of the linker length slightly reduces lectin capacity as agglutinin and slows down aggregate formation at low ligand surface density. The mutant protein is considerably less active as agglutinin and less sensitive to low-level ligand presentation. The present results suggest that mimicking glycan complexity and microdomain occurrence on the glycodendrimersome surface can provide key insights into mechanisms to accomplish natural selectivity and specificity of lectins in structural and topological terms.adhesion | agglutination | glycobiology | membrane mimic | self-assembly

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confidence: 99%

Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface

Zhang

Moussodia

Vértesy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Gal-8 variant F19Y is significantly associated with rheumatoid arthritis [13]. If Phe19 were mutated to Tyr, then the hydroxyl group of Tyr could influence the interaction between Phe19 and Ile12, such that the structure of the N-terminal tail would be influenced.…”

Section: Resultsmentioning

confidence: 99%

“…Wild type Gal-8 N 1-152 has been crystallized in the P 4 3 2 1 2 space group [13] when glycerol was also used as the cryoprotectant. However, in that study, glycerol did not replace lactose, and was found to be located close to Tyr141 [13]. Moreover, in that instance, glycerol did not influence lactose binding to the Gal-8 N-terminal CRD.…”

Section: Resultsmentioning

confidence: 99%

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Crystallization of Galectin-8 Linker Reveals Intricate Relationship between the N-terminal Tail and the Linker

Wang

Gao

et al. 2016

IJMS

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Galectin-8 (Gal-8) plays a significant role in normal immunological function as well as in cancer. This lectin contains two carbohydrate recognition domains (CRD) connected by a peptide linker. The N-terminal CRD determines ligand binding specificity, whereas the linker has been proposed to regulate overall Gal-8 function, including multimerization and biological activity. Here, we crystallized the Gal-8 N-terminal CRD with the peptide linker using a crystallization condition that contains Ni2+. The Ni2+ ion was found to be complexed between two CRDs via crystal packing contacts. The coordination between Ni2+ and Asp25 plays an indirect role in determining the structure of β-strand F0 and in influencing the linker conformation which could not be defined due to its dynamic nature. The linker was also shortened in situ and crystallized under a different condition, leading to a higher resolution structure refined to 1.08 Å. This crystal structure allowed definition of a short portion of the linker interacting with the Gal-8 N-terminal tail via ionic interactions and hydrogen bonds. Observation of two Gal-8 N-terminal CRD structures implies that the N-terminal tail and the linker may influence each other’s conformation. In addition, under specific crystallization conditions, glycerol could replace lactose and was observed at the carbohydrate binding site. However, glycerol did not show inhibition activity in hemagglutination assay.

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“…Altered Gal-8 functions have been found in rheumatic, autoimmune and inflammatory human disorders [32, 33]. A single aminoacid polymorphism (F19Y) with functional implications on cancer cell growth [34] and glycan interactions [35], strongly associates with rheumatoid arthritis [36]. Interestingly, neutralizing anti-Gal-8 autoantibodies that block Gal-8 interactions with glycans on β1-integrins and LFA-1 [37, 38], as well as Gal-8-induced apoptosis of T cells [29], are frequently generated in systemic lupus erythematosus (SLE), the prototypic autoimmune disease, and also in rheumatoid arthritis and probably other inflammatory disorders [39].…”

Section: Introductionmentioning

confidence: 99%

Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis

et al. 2017

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Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.

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Non-synonymous single nucleotide polymorphisms in genes for immunoregulatory galectins: Association of galectin-8 (F19Y) occurrence with autoimmune diseases in a Caucasian population

Cited by 27 publications

References 40 publications

Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface

Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface

Crystallization of Galectin-8 Linker Reveals Intricate Relationship between the N-terminal Tail and the Linker

Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis

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