Liu Yuemin, Pan Di, Bellis Susan L, Song Yuhua
Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Proteins. 2008 Dec;73(4):989-1000. doi: 10.1002/prot.22126.
Glycosylation plays an important role in the regulation of integrin function. Molecular mechanisms underlying the effects of altered glycosylation on beta1 integrin structure and function are still largely unknown. In this study, we used a molecular modeling approach to study the effects of altered glycosylation, with alpha2-6 sialic acid and without alpha2-6 sialic acid, on the structure of the I-like domain of the beta1 integrin. Our results demonstrated that altered glycosylation affected the interactions between oligosaccharides and the I-like domain, which in turn changed the accessibility of the specificity-determining loop for ligand binding. Altered glycosylation caused significant conformational changes for most of the key functional regions of the I-like domain of beta1 integrin, including the metal ion-dependent adhesion site that contains a DLSYS motif, and other critical residues for ligand binding (Asn-224, Glu-229, Asp-233, Asp-267, and Asp-295). In addition, altered glycosylation caused significant movement of the alpha1 and alpha7 helices, which are important for the activation of beta1 integrin. The results from this study offered molecular mechanisms for the experimental observations that variant glycosylation regulates integrin function.
糖基化在整合素功能的调节中起着重要作用。糖基化改变对β1整合素结构和功能影响的分子机制仍 largely unknown。在本研究中，我们使用分子建模方法来研究有α2-6唾液酸和无α2-6唾液酸的糖基化改变对β1整合素I样结构域结构的影响。我们的结果表明，糖基化改变影响了寡糖与I样结构域之间的相互作用，进而改变了配体结合特异性决定环的可及性。糖基化改变导致β1整合素I样结构域的大多数关键功能区域发生显著构象变化，包括含有DLSYS基序的金属离子依赖性粘附位点以及其他配体结合关键残基（Asn-224、Glu-229、Asp-233、Asp-267和Asp-295）。此外，糖基化改变导致α1和α7螺旋发生显著移动，这对β1整合素的激活很重要。本研究结果为变异糖基化调节整合素功能的实验观察提供了分子机制。
