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Structural aspects of the interaction of the cytoplasmic domain of Mucin-1 (MUC1) with the SH3 domain of Src Kinase Open Access


Other title
Src Kinase
SH3 domain
Type of item
Degree grantor
University of Alberta
Author or creator
Marasinghe Arachchige, Bodhi Nirosha
Supervisor and department
Hugh, Judith C. (Laboratory Medicine and Pathology)
Examining committee member and department
Sykes, Brian D. (Biochemistry)
Shaw, Andrew (Oncology)
Bamforth, Fiona (Laboratory Medicine and Pathology)
Wishart, David (Biological Sciences)
Medical Sciences-Laboratory Medicine and Pathology

Date accepted
Graduation date
Master of Science
Degree level
Abstract Breast cancer is the second most frequent cause of cancer deaths in Canadian women with death resulting from the spread of cancer cells or metastasis to distal organs. Our laboratory was the first to show that MUC1, a type-1 transmembrane glycoprotein highly overexpressed in breast tumors, may contribute to migration of breast cancer cells by binding to the Intercellular adhesion molecule-1 (ICAM-1), which triggers the recruitment of non-receptor tyrosine kinase, Src that initiates the downstream signaling. However, the structural aspects of the interaction of cytoplasmic domain of MUC1 (MUC1-CD) and the Src-SH3 domain are still unknown. This thesis, aims to determine the affinity and specificity of this interaction using multinuclear, multidimensional nuclear magnetic resonance (NMR) spectroscopy/titration studies using 15N labeled Src-SH3 domain and the synthetic peptides of MUC1-CD. The results revealed that the dissociation constant (KD) for the interaction of 69-residue full-length MUC1-CD and Src-SH3 domain is 1.85 mM, based on the residues that show the highest chemical shift changes (> 0.04 ppm). Although the residue-shifts were very small (< 0.1 ppm) different-length MUC1-peptides produced the same results. The most perturbed residues were, Arg98, Glu100, Leu103, His125, Thr132 and Gly130 located outside the canonical binding site, suggesting that MUC1-CD binds with a high specificity but a low affinity to a non-canonical site. The results form a foundation for further structural studies exploring the molecular recognition mechanisms of the MUC1/Src-SH3 interaction.
License granted by Bodhi Nirosha Gunasekara Marasinghe Arachchige ( on 2011-08-30T19:19:28Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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