Polypeptides synthesized by membrane-bound ribosomes are cotranslationally integrated ir to the endoplasmic reticulum membrane. Transmembrane segments are positioned in the membrane via two distinct modes. In the autonomous mode, hydrophobic segments are integrated into the membrane based on the characteristics of the segment. In the heteronomous mode, a segment that is not inserted into the membrane by itself is forced into a transmembrane disposition by other segments. This unexpected insertion is achieved by a signal-anchor sequence with N-exo/C-cyto topology that translocates the preceding segment. Structural and functional diversities of transmembrane segments in multispanning proteins are acquired via this mode. Such a heteronomous positioning of polypeptide segments might occur not only in the integration process of membrane proteins but also in the general folding processes of soluble proteins. (C) 2002 Elsevier Science (USA). All rights reserved.