Mechanical compressibility of the glycosylphosphatidylinositol (GPI) anchor backbone governed by independent glycosidic linkages.
About 1% of the human proteome is anchored to the outer leaflet of cell membranes via a class of glycolipids called GPI anchors. In spite of their ubiquity, experimental information about the conformational dynamics of these glycolipids is rather limited. Here, we use a variety of computer simulation techniques to elucidate the conformational flexibility of the Man-α(1→2)-Man-α(1→6)-Man-α(1→4)-GlcNAc-α-OMe tetrasaccharide backbone 2 that is an essential and invariant part of all GPI-anchors. In addition to the complete tetrasaccharide structure, all disaccharide and trisaccharide subunits of the GPI backbone have been studied as independent moieties. The extended free energy landscape as a function of the corresponding dihedral angles has been determined for each glycosidic linkage relevant for the conformational preferences of the tetrasaccharide backbone (Man-α(1→2)-Man, Man-α(1→6)Man and Man-α(1→4)-GlcNAc). We compared the free energy landscapes obtained for the same glycosidic linkage within different oligosaccharides. This comparison reveals that the conformational properties of a linkage are primarily determined by its two connecting carbohydrate moieties, just as in the corresponding disaccharide. Furthermore, we can show that the torsions of the different glycosidic linkages within the GPI tetrasaccharide can be considered as statistically independent degrees of freedom. Using this insight, we are able to map the atomistic description to an effective, reduced model and study the response of the tetrasaccharide 2 to external forces. Even though the backbone assumes essentially a single, extended conformation in the absence of mechanical stress, it can be easily bent by forces of physiological magnitude.
Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
Marko
M
Wehle
Ivan
I
Vilotijevic
Reinhard
R
Lipowsky
Peter H
PH
Seeberger
Daniel Varon
DV
Silva
Mark
M
Santer
D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D006027:Glycosides / Q000737:chemistry*; D017261:Glycosylphosphatidylinositols / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data
D006027:Glycosides; D017261:Glycosylphosphatidylinositols