A Multivalent Marine Lectin from <i>Crenomytilus grayanus</i> Possesses Anti-cancer Activity through Recognizing Globotriose Gb3

Liao, Jiahn-Haur; Chien, Chih-Ta Henry; Wu, Hung‐Yi; Huang, Kai‐Fa; Wang, Iren; Ho, Meng‐Ru; Tu, I-Fan; Lee, I‐Ming; Li, Wei; Shih, Yu‐Ling; Wu, Chung‐Yi; Lukyanov, Pavel; Hsu, Shang-Te Danny; Wu, Shih‐Hsiung

doi:10.1021/jacs.6b00111

Cited by 51 publications

(62 citation statements)

References 51 publications

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“…The Mitsuba-1 model, like MytiLec, shows no evidence of a significant role for water at any of the three sites in the asymmetric unit 9 . Each sugar ligand is well-ordered in the electron density map determined for Mitsuba-1 (Supplementary Figure 5), suggesting tight binding, but from earlier work with MytiLec 9 and CGL 28, 30 it is known that each binding site alone has rather weak affinity, and the avidity of the protein for cell surfaces displaying suitable sugar ligands arises from the multiplicity of sites. Using calorimetry, Mitsuba-1 was found to bind N-acetylgalactosamine with a K d of 0.33 mM (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Unsurprisingly, the top hits are models of MytiLec 9 and CGL 27, 28 (for example PDB models 3WMV and 5DUY), sharing a Z-score of 27.2, and a number of β -trefoil proteins are detected. Less expected was that the Threefoil model, with a Z-score of 23.5, ranked slightly behind Ct1, an exo-beta-1,3-galactanase from Clostridium thermocellum .…”

Section: Resultsmentioning

confidence: 99%

“…The mode of sugar binding is common to MytiLec-1 and CGL 27, 28 . The contacts between Mitsuba-1 with GalNAc include five hydrogen bonds, including hydrogen bonds with two histidines and two aspartate residues.…”

Section: Resultsmentioning

confidence: 99%

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Computational design of a symmetrical β-trefoil lectin with cancer cell binding activity

Terada

Voet

Noguchi

et al. 2017

Sci Rep

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Computational protein design has advanced very rapidly over the last decade, but there remain few examples of artificial proteins with direct medical applications. This study describes a new artificial β-trefoil lectin that recognises Burkitt’s lymphoma cells, and which was designed with the intention of finding a basis for novel cancer treatments or diagnostics. The new protein, called “Mitsuba”, is based on the structure of the natural shellfish lectin MytiLec-1, a member of a small lectin family that uses unique sequence motifs to bind α-D-galactose. The three subdomains of MytiLec-1 each carry one galactose binding site, and the 149-residue protein forms a tight dimer in solution. Mitsuba (meaning “three-leaf” in Japanese) was created by symmetry constraining the structure of a MytiLec-1 subunit, resulting in a 150-residue sequence that contains three identical tandem repeats. Mitsuba-1 was expressed and crystallised to confirm the X-ray structure matches the predicted model. Mitsuba-1 recognises cancer cells that express globotriose (Galα(1,4)Galβ(1,4)Glc) on the surface, but the cytotoxicity is abolished.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Computational design of a symmetrical β-trefoil lectin with cancer cell binding activity

Terada

Voet

Noguchi

et al. 2017

Sci Rep

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“…1B). Copurification of endogenous carbohydrates with recombinant proteins has been uncommonly encountered in previous studies (39) because of generally relatively low binding affinity (∼millimolar) between noncognate glycans and GBPs (40). Nonetheless, our studies strongly suggest Y3 to be a GBP.…”

Section: Resultsmentioning

confidence: 51%

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

Zhang

Yang

et al. 2017

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

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Glycans possess significant chemical diversity; glycan binding proteins (GBPs) recognize specific glycans to translate their structures to functions in various physiological and pathological processes. Therefore, the discovery and characterization of novel GBPs and characterization of glycan-GBP interactions are significant to provide potential targets for therapeutic intervention of many diseases. Here, we report the biochemical, functional, and structural characterization of a 130-amino-acid protein, Y3, from the mushroom Coprinus comatus. Biochemical studies of recombinant Y3 from a yeast expression system demonstrated the protein is a unique GBP. Additionally, we show that Y3 exhibits selective and potent cytotoxicity toward human T-cell leukemia Jurkat cells compared with a panel of cancer cell lines via inducing caspase-dependent apoptosis. Screening of a glycan array demonstrated GalNAcβ1-4(Fucα1-3)GlcNAc (LDNF) as a specific Y3-binding ligand. To provide a structural basis for function, the crystal structure was solved to a resolution of 1.2 Å, revealing a single-domain αβα-sandwich motif. Two monomers were dimerized to form a large 10-stranded, antiparallel β-sheet flanked by α-helices on each side, representing a unique oligomerization mode among GBPs. A large glycan binding pocket extends into the dimeric interface, and docking of LDNF identified key residues for glycan interactions. Disruption of residues predicted to be involved in LDNF/Y3 interactions resulted in the significant loss of binding to Jurkat T-cells and severely impaired their cytotoxicity. Collectively, these results demonstrate Y3 to be a GBP with selective cytotoxicity toward human T-cell leukemia cells and indicate its potential use in cancer diagnosis and treatment.

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“…We used cDNA sequencing to determine the amino acid sequence of CGL and found that CGL exhibited antibacterial and antifungal activities in the shellfish by being involved in the recognition and clearance of bacterial pathogens 18, 19 . Recently, we determined the crystal structure of CGL, which revealed the presence of a β-trefoil fold that dimerizes into a dumbbell-shaped quaternary structure in the protein 20 .…”

Section: Introductionmentioning

confidence: 99%

A GalNAc/Gal-specific lectin from the sea mussel Crenomytilus grayanus modulates immune response in macrophages and in mice

Chernikov

Wong

et al. 2017

Sci Rep

Self Cite

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A GalNAc/Gal-specific lectin (CGL) from the edible mussel Crenomytilus grayanus has been demonstrated to exhibit antibacterial properties. However, the mechanism of immune modulation by CGL in mammalian cells remains unclear. Here, we demonstrated that CGL can activate immune responses in macrophages and in mice. In the in vitro cell models, CGL induced tumour necrosis factor-α and interleukin-6 secretion in mouse RAW264.7 macrophages, mouse bone marrow-derived macrophages, human THP-1 macrophages, human peripheral blood mononuclear cells and human blood monocyte-derived macrophages. The CGL-mediated cytokine production was regulated by reactive oxygen species, mitogen-activated protein kinases, protein kinase C-α/δ and NF-κB. Interestingly, in lipopolysaccharide-activated macrophages, CGL induced endotoxin tolerance (characterized by the downregulation of nitric oxide, inducible nitric oxide synthase, interleukin-6 and cyclooxygenase II) via the downregulation of IRAK2 expression, JNK1/2 phosphorylation and NF-κB activation. CGL also slightly increased the bactericidal activity of macrophages and induced cytokine production in mouse models. Overall, our data indicate that CGL has the potential to be used as an immune modulator in mammals.

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A Multivalent Marine Lectin from Crenomytilus grayanus Possesses Anti-cancer Activity through Recognizing Globotriose Gb3

Cited by 51 publications

References 51 publications

Computational design of a symmetrical β-trefoil lectin with cancer cell binding activity

Computational design of a symmetrical β-trefoil lectin with cancer cell binding activity

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

A GalNAc/Gal-specific lectin from the sea mussel Crenomytilus grayanus modulates immune response in macrophages and in mice

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