PREDICTION OF SIGNAL PEPTIDE FUNCTIONAL-PROPERTIES - A STUDY OF THE ORIENTATION AND ANGLE OF INSERTION OF YEAST INVERTASE MUTANTS AND HUMANAPOLIPOPROTEIN-B SIGNAL PEPTIDE VARIANTS

A number of studies have introduced mutations into the yeast invertase signal peptide, using it as a model system to elucidate features for targeting, translocation and intracellular transport. Using molecular modelling of the invertase signal peptide we have analysed the hydroph obicity potential and the change in the dielectric constant of the ene rgy transfer, when the molecule moves from a hydrophobic to a hydrophi lic phase at the simulated hydrophobic-hydrophilic interface. This mod elling has been carried out on wild type and mutant invertase signal p eptides of altered function, previously reported in the literature, Wh ile the predicted angle of insertion correlates with the measured exte nt of invertase secretion, with an optimum angle of 45 degrees, mutati ons that change the angle of orientation reduce the extent of invertas e secretion, We have applied these same molecular modelling principles to the naturally occurring variants of the human apolipoprotein B (ap oB) signal peptide, that confer a secretion defective phenotype when f used to yeast invertase and expressed in yeast, Our modelling thus ide ntifies a strong correlation between the predicted angle of insertion of the signal peptide into the membrane and its ability to direct secr etion.