Heads or tails - what determines the orientation of proteins in the membrane

The same translocation machinery in the endoplasmic reticulum translocates either the N-or the C-terminal domain of signal-anchor proteins across the membranes. Charged residues flanking the signal sequence are important to determine which end is translocated, but are not sufficient to generate a uniform topology. The folding state of the N-terminal segment, which is to be translocated posttranslationally, and the length or hydrophobicity of the signal sequence are additional criteria to determine protein orientation in the membrane.