Why does the 'Positive-inside Rule' exist?

Question

Gunnar von Heijne's Positive-inside Rule seems to have been around for a couple of decades and underpins a lot of what we know about transmembrane topology. It is used to predict the topology of a given transmembrane domain, typically a helix.

My question is what are the physicochemical, or biochemical explanations for this rule? Although the literature talks about it in depth and has many examples of the rule being employed, I can't seem to find anything about the "behind the scenes" explanation.

Answer 1

There are not much explanations available, as far as I can see. The best explanation that I have found is that the positive charge allows the orientation of the protein in the membrane. The orientation for membrane proteins is important as a lot of them are transporters which have a dedicated transportation direction. The same is true for receptors, which transport a signal from the outside to the inside of the cell. Most of the positively charged arginine and lysine residues are found in loop regions which are located between transmembrane regions (often hydrophobic helices).

References:

1. Topogenic signals in integral membrane proteins.
2. Positive charge loading at protein termini is due to membrane protein topology, not a translational ramp
3. The Positive Inside Rule Is Stronger When Followed by a Transmembrane Helix
4. Membrane-protein topology

Answer 2

Proteins insert according to the positive inside rule because positive charges tend to stay in the cytoplasm. Cells tend to have an electrostatic polarity across the membrane boundary that will hold the positive area inside, and because higher pK values make the positive areas harder to deprotonate, these interactions tend to make the protein stay that way.