As proteins are integrated into the membrane of the endoplasmic reticu
lum, some hydrophilic polypeptide segments are transported through the
translocation channel, others remain in the cytosol, and hydrophobic
transmembrane sequences are released into the lipid phase. We have add
ressed the molecular mechanism by which these events occur. We demonst
rate that both the lumenal and the cytosolic domains of a membrane pro
tein are synthesized while the ribosome is membrane bound, so that eve
n cytosolic domains come in contact with the translocation channel. We
also find that, before translation of the protein is terminated, tran
smembrane sequences can laterally exit the translocation channel and e
nter the lipid environment. These results have significant implication
s for the folding and assembly of membrane proteins.