In previous chapters, we have encountered many of the vast array of integral membrane (transmembrane) proteins that are present throughout the cell. Each such protein has a unique orientation with respect to the membrane’s phospholipid bilayer. Integral membrane proteins located in the ER, Golgi complex, and lysosomes, as well as in the plasma membrane, which are all synthesized on the rough ER, remain embedded in the membrane as they move to their final destinations along the same pathway that is followed by soluble secretory proteins (see Figure 13-1, left). During this transport, the orientation of a membrane protein is preserved; that is, the same segments of the protein always face the cytosol, whereas other segments always face in the opposite direction. Thus the final orientation of these membrane proteins is established during their biosynthesis on the ER membrane. In this section, we first see how integral membrane proteins interact with membranes and then examine how several types of sequences, known collectively as topogenic sequences, direct the membrane insertion and orientation of various classes of integral membrane proteins. These processes occur via modifications of the basic mechanism used to translocate soluble secretory proteins across the ER membrane.