Abstract
IntroductionE-selectin is a member of the selectin family of cell adhesion molecules expressed on the plasma membrane of inflamed endothelium and facilitates initial leukocyte tethering and subsequent cell rolling during the early stages of the inflammatory response via binding to glycoproteins expressing sialyl LewisX and sialyl LewisA (sLeX/A). Existing crystal structures of the extracellular lectin/EGF-like domain of E-selectin complexed with sLeX have revealed that E-selectin can exist in two conformation states, a low affinity (bent) conformation, and a high affinity (extended) conformation. The differentiating characteristic of the two conformations is the interdomain angle between the lectin and the EGF-like domain.MethodsUsing molecular dynamics (MD) simulations we observed that in the absence of tensile force E-selectin undergoes spontaneous switching between the two conformational states at equilibrium. A single amino acid substitution at residue 2 (serine to tyrosine) on the lectin domain favors the extended conformation.ResultsSteered molecular dynamics (SMD) simulations of E-selectin and PSGL-1 in conjunction with experimental cell adhesion assays show a longer binding lifetime of E-selectin (S2Y) to PSGL-1 compared to wildtype protein.ConclusionsThe findings in this study advance our understanding into how the structural makeup of E-selectin allosterically influences its adhesive dynamics.
Highlights
E-selectin is a member of the selectin family of cell adhesion molecules expressed on the plasma membrane of inflamed endothelium and facilitates initial leukocyte tethering and subsequent cell rolling during the early stages of the inflammatory response via binding to glycoproteins expressing sialyl LewisX and sialyl LewisA
E-selectin belongs to a family of cell adhesion (E, L, and P-) molecules that are responsible for leukocyte recruitment to inflammation sites.[18]
Existing structural data suggest that selectins adopt two conformational states: a low affinity, and a high affinity conformation
Summary
E-selectin is a member of the selectin family of cell adhesion molecules expressed on the plasma membrane of inflamed endothelium and facilitates initial leukocyte tethering and subsequent cell rolling during the early stages of the inflammatory response via binding to glycoproteins expressing sialyl LewisX and sialyl LewisA (sLeX/A). Existing crystal structures of the extracellular lectin/EGF-like domain of E-selectin complexed with sLeX have revealed that Eselectin can exist in two conformation states, a low affinity (bent) conformation, and a high affinity (extended) conformation. In the ‘‘prybar’’ model, residue 1W of the lectin domain and the EGF-like domain of L-selectin together form an L-shaped lever that is held together by a network of hydrogen bonds when the molecule is in the bent conformation. When force is applied and L-selectin transitions to the extended conformation, the lever dislodges the relatively large and hydrophobic residue, 1W, which causes a cascade of residue displacements resulting in the allosteric change of the binding interface to a high-affinity conformation
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