Signal recognition particle-dependent membrane insertion of mouse invariant chain: a membrane-spanning protein with a cytoplasmically exposed amino terminus

What mechanism can be envisaged for a common step in membrane insertion of secretory and type 1 and 2 membrane proteins? A very attractive possibility, first proposed by Inouye and his colleagues for the lipoprotein of Escherichia coli and further extended to membrane-spanning proteins, is that the insertion of the NH2-terminal portion of nascent secretory or membrane-spanning proteins into the membrane of the ER occurs in a loop-like fashion (14, 22, 45) . This model is based on the assumption that the NHE-terminal end of the signal sequence, cleavable or noncleavable, remains exposed on the cytoplasmic side of the ER membrane. Cleavage of the signal sequence then releases the new NH2-terminal end of the mature protein to the lumen of the ER vesicle. The cleaved signal sequence might remain in some or all cases buried in the membrane. Type l membrane-spanning proteins, like the H-2 antigens or VSV G protein, have in addition to a cleavable signal sequence a second stretch of uncharged amino acid residues located close to the COOH-terminal end. This functions as a "stop transfer" sequence and anchors the protein in the membrane. In type 2 membrane proteins with uncleaved signal sequence the single hydrophobic segment might perform two functions: (a) as a single sequence mediating SRPdependent membrane insertion, and (b) as a stop transfer sequence anchoring the protein in the membrane. Certainly further direct evidence is required for support of this model for membrane insertion of type 2 membrane proteins.