Journal
BIOPHYSICAL JOURNAL
Volume 99, Issue 1, Pages 208-217Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2010.03.063
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Funding
- Ireland Tuition Scholarship
- National Science Foundation [MCB080078]
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N-glycosylation of the I-like domain of beta 1 integrin plays an essential role in integrin structure and function, and the altered sialylation of beta 1 integrin regulates beta 1 integrin binding to fibronectin. However, the structural basis underlying the effect of altered sialylation of the beta 1 I-like domain on beta 1 integrin binding to fibronectin remains largely unknown. In this study, we used a combination of molecular dynamics simulations and binding free energy analyses to investigate changes in binding thermodynamics and in conformation of the glycosylated beta 1 I-like domain-FN-III9-10 complex caused by altered sialylation of the beta 1 I-like domain. Binding free energy analyses showed that desialylation of beta 1 I-like domain increased beta 1 integrin binding to fibronectin, consistent with experimental results. Interaction analyses showed that altered sialylation of the beta 1 I-like domain resulted in significant changes in the interaction of the N-glycans of the I-like domain with both the I-like domain and fibronectin, and these changes could directly affect the allosteric regulation of the interaction between the I-like domain and fibronectin. Altered sialylation of the beta 1 I-like domain caused significant conformational changes in key functional sites of both the beta 1 I-like domain and fibronectin. In addition, altered sialylation of the beta 1 I-like domain resulted in changes in the degree of correlated motions between residues in the I-like domain and residues in fibronectin, and in the degree of motion changes in fibronectin, which could affect beta 1 integrin binding to fibronectin. We believe results from this study provide thermodynamic and structural evidence for a role of altered sialylation of beta 1 integrin in regulating beta 1 integrin binding to fibronectin and it's induced cellular activities.
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