Structural Study of Differential Lactose Binding Affinities of Human Galectin-1, -7, and -8.
Date Issued
2014
Date
2014
Author(s)
Chien, Chih-Ta
Abstract
Galectins are a family of lectins that interact with β-galactosides, express in cytosol, nucleus, and extracellular matrix, and confer a broad range of functions including cell-cell interaction, cell-matrix adhesion and transmembrane signaling. Despite their low sequence homology, their three-dimensional structures are essentially identical. The binding affinity of galectins to lactose and other β-galactosides vary significantly. However, it is difficult to rationalize the molecular recognition mechanisms of different galectins based on their crystal structures of the apo- and holo-forms, which exhibit minimal conformational changes even for the side-chains that are involved in ligand binding. In order to better understand the origin of substrate binding affinity and selectivity, we systematically investigate the differential effects of lactose binding on human galectin-1, -7, and -8 in terms of their internal dynamics and folding stabilities using molecular dynamics (MD) simulation, far-UV circular dichroism (CD), intrinsic fluorescence and nuclear magnetic resonance (NMR) spectroscopy. NMR hydrogen-deuterium exchange (HDX) data suggest that lactose binding not only perturbs the structures and dynamics of the residues that are directly involved ligand binding but also results in long-range perturbations at the dimer interface for galectin-1 and -7. This is consistent with the differences in fast internal dynamics in MD simulations and 15N spin relaxation dynamics, as well as the folding stabilities of galectin-1, -7, -8 in response to lactose binding. Such differential responses to ligand binding for different galectins may be implicated in modulating the binding affinity and selectivity, and hence could potentially be exploited for designs of better inhibitors with higher specificity.
Subjects
半乳糖凝集素
核磁共振
蛋白摺疊
Type
thesis
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