Practice question

Topological orientation of membrane proteins, defined by which loops face cytosolic versus exoplasmic or lumenal space, is encoded within polypeptide itself as a set of topogenic signals rather than imposed solely by external receptors. As nascent chain enters Sec61 translocon, hydrophobic segments can function either as start-transfer signal-anchor that opens lateral gate and initiates translocation of downstream region, or as stop-transfer sequence that halts translocation and partitions laterally into lipid bilayer through same gate formed by helices 2b and 7. Positive-inside rule, first documented in bacteria and conserved in eukaryotes, shows distribution of positively charged lysine and arginine residues flanking hydrophobic core strongly influences orientation because moving positive charge across membrane costs more energy and because Sec61 retains basic flanks cytosolically via acidic residues lining pore and anionic phospholipid attraction. Order of successive signal-anchor and stop-transfer elements determines multi-spanning topology polytopic proteins. SRP receptor presence or ATP hydrolysis modulates efficiency of targeting but does not rewrite inherent topological information encoded by charge bias and hydrophobicity profile of signal-anchor and stop-transfer sequences.