The amino-terminal domain of the lamin B receptor is a nuclear envelope targeting signal

The present findings must be interpreted in light of the putative topology of LBR. LBR is synthesized without a cleavable amino-terminal signal sequence and therefore the amino-terminal domain likely faces the cytoplasm when synthesized on the ER membrane. With this topology, the first putative transmembrane domain would function as both an uncleaved signal sequence and a stop transfer sequence (Blobel, 1980) . Hence, LBR is synthesized on the ER membrane with a topology analogous to type II integral membrane proteins of the plasma membrane. This topology of LBR is supported by the finding that a residue in its amino-terminal domain is phosphorylated in vivo by p34 '~c2 protein kinase (Courvalin et al., 1992) , an enzyme that is present in the nucleus and cytoplasm and not likely the ER lumen or the perinuclear space. When reaching the inner nuclear membrane, the amino-terminal domain of LBR would have a nucleoplasmic orientation like the amino termini of type II plasma membrane proteins have a cytoplasmic orientation. As LBR amino-terminal domain can reach the nucleus after synthesis in the cytoplasm, cytoplasmically exposed amino-terminal domain should also be able to reach the nucleus by the same mechanism when attached to transmembrane segments in the ER membrane. The nuclear translocation of LBR amino-terminal domain would then "drag" the transmembrane segments of the protein that remain embedded in the proteolipid bilayer to the inner nuclear membrane. The ultrastructure of the nuclear pore complex would have to be such that there is no steric hindrance and that membrane-embedded proteins can freely diffuse in the pore membrane domain.