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Calorimetric analysis of the interplay between synthetic Tn antigen-presenting MUC1 glycopeptides and human macrophage galactose-type lectin

Human macrophage galactose-type lectin (hMGL, HML, CD301, CLEC10A), a C-type lectin expressed by dendritic cells and macrophages, is a receptor for N-acetylgalactosamine alpha-linked to serine/threonine residues (Tn antigen, CD175) and its alpha 2,6-sialylated derivative (sTn, CD175s). Because these...

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Main Authors: Beckwith, Donella M (Author) , FitzGerald, Forrest G. (Author) , Rodriguez Benavente, Maria C. (Author) , Mercer, Elizabeth R. (Author) , Ludwig, Anna-Kristin (Author) , Michalak, Malwina (Author) , Kaltner, Herbert (Author) , Kopitz, Jürgen (Author) , Gabius, Hans-Joachim (Author) , Cudic, Maré (Author)
Format: Article (Journal)
Language:English
Published: February 9, 2021
In: Biochemistry
Year: 2021, Volume: 60, Issue: 7, Pages: 547-588
ISSN:1520-4995
DOI:10.1021/acs.biochem.0c00942
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.biochem.0c00942
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Author Notes:Donella M. Beckwith, Forrest G. FitzGerald, Maria C. Rodriguez Benavente, Elizabeth R. Mercer, Anna-Kristin Ludwig, Malwina Michalak, Herbert Kaltner, Jürgen Kopitz, Hans-Joachim Gabius, and Maré Cudic
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Summary:Human macrophage galactose-type lectin (hMGL, HML, CD301, CLEC10A), a C-type lectin expressed by dendritic cells and macrophages, is a receptor for N-acetylgalactosamine alpha-linked to serine/threonine residues (Tn antigen, CD175) and its alpha 2,6-sialylated derivative (sTn, CD175s). Because these two epitopes are among malignant cell glycan displays, particularly when presented by mucin-1 (MUC1), assessing the influence of the site and frequency of glycosylation on lectin recognition will identify determinants governing this interplay. Thus, chemical synthesis of the tandem-repeat O-glycan acceptor region of MUC1 and site-specific threonine glycosylation in all permutations were carried out. Isothermal titration calorimetry (ITC) analysis of the binding of hMGL to this library of MUC1 glycopeptides revealed an enthalpy-driven process and an affinity enhancement of an order of magnitude with an increasing glycan count from 6-8 mu M for monoglycosylated peptides to 0.6 mu M for triglycosylated peptide. ITC measurements performed in D2O permitted further exploration of the solvation dynamics during binding. A shift in enthalpy-entropy compensation and contact position-specific effects with the likely involvement of the peptide surroundings were detected. KinITC analysis revealed a prolonged lifetime of the lectin-glycan complex with increasing glycan valency and with a change in the solvent to D2O.
Item Description:Gesehen am 05.08.2021
Physical Description:Online Resource
ISSN:1520-4995
DOI:10.1021/acs.biochem.0c00942

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