Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides.

Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Research Abstract Details 

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Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Abstract Text:

D I Spencer,S Missailidis,G Denton,A Murray,K Brady,C I Matteis,M S Searle,S J Tendler,M R Price,

MUC1 mucin is a large complex glycoprotein expressed on normal epithelial cells in humans and overexpressed and under or aberrantly glycosylated on many malignant cancer cells which consequently allows recognition of the protein core by antibodies. In order to understand how glycosylation may modulate or regulate antibody binding of mucin protein core epitopes, we have analyzed the antibody C595 (epitope RPAP) for its structure, stability, and its binding to a series of synthetic peptides and glycopeptides by a number of spectroscopic methods. Thermal and pH denaturation studies followed by changes in the CD spectrum of the antibody indicate critical involvement of specific residues to the stability of the antibody. Fluorescence binding studies indicate that alpha-N-acetylgalactosamine (GalNAc) glycosylation of a MUC1 mucin synthetic peptide TAPPAHGVT9SAPDTRPAPGS20T21APPA at threonine residues 9 and 21 and serine residue 20 enhanced the binding of antibody. The structural effects of GalNAc glycosylation on the conformation of the MUC1 peptide were studied. CD of the peptides and glycopeptides in a cryogenic mixture cooled to approximately -97 degrees C revealed that a left-handed polyproline II helix (PPII) is adopted by the peptides in solution, which appears to be further stabilized by addition of the GalNAc residues. Consistent with the PPII helical structure, which has no intra-amide hydrogen bonds, high-field NMR spectroscopy of the glycopeptide revealed no sequential dNN, medium-range, or long-range nuclear Overhauser effect (NOE) connectivities. These studies indicate that stabilization of the PPII helix by GalNAc glycosylation present the epitope of C595 antibody with a favorable conformation for binding. Furthermore, they illustrate that glycosylation of the MUC1 tumor marker protein with a simple O-linked saccharide expressed in many cancers, can enhance the binding of the clinically relevant C595 antibody.

Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Publishing Authors By Initials

DI Spencer,S Missailidis,G Denton,A Murray,K Brady,CI Matteis,MS Searle,SJ Tendler,MR Price,

For similar amino acids, peptides, and proteins: amino acids: amino acids, cyclic: amino acids, aromatic: tyrosine research abstracts see: amino acids, peptides, and proteins: amino acids: amino acids, cyclic: amino acids, aromatic: tyrosine research

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Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biospectroscopy

VOLUME: 5

Page Numbers: 79-91

Journal Abbreviation:

ISSN: 1075-4261

DAY: 1

MONTH: 12

YEAR: 1999

Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Information

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LANGUAGE: eng

NlmUniqueID: 9605413

Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Keywords Mesh Terms:

KEYWORDS: Tyrosine

MESH TERMS: chemistry

Chemical & Substance for Abstract: Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides. Information

Substance Name: Tryptophan

Registry Number: 73-22-3

Grant and Affiliation Information for Structure/activity studies of the anti-MUC1 monoclonal antibody C595 and synthetic MUC1 mucin-core-related peptides and glycopeptides.

AFFILIATION: Cancer Research Laboratories, University of Nottingham, United Kingdom.

Country: UNITED STATES

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MEDLINETA: Biospectroscopy

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