ON THE PHYSICAL BASIS FOR THE CIS-POSITIVE RULE DESCRIBING PROTEIN ORIENTATION IN BIOLOGICAL-MEMBRANES

The topology of hydrophobic intramembrane proteins is characterized by a statistical asymmetry in the distribution of positively-charged res idues on the two sides of the membrane, the 'inside- or cis-positive r ule'. A mechanism is proposed involving only neutral residue transfer. For a tightly bound polypeptide adsorbed on the membrane and not at e quilibrium, the pK values of the ionic residues related to dissociatio n of the proton into the aqueous phase bulk are increased because of i nteraction with the negative charges at the membrane surface. The pg s hift would selectively neutralize aspartate and glutamate residues, fa voring their translocation across the membrane, while stabilizing the impermeant positively charged state of lysine and arginine residues.