What is the role of signal sequences in protein sorting?
Protein sorting fidelity in eukaryotic cells depends on specific topogenic signals encoded within polypeptide sequences acting as molecular zip codes recognized by targeting machinery. N-terminal signal peptide typical for secretory pathway contains approximately 15 to 30 amino acids organized into positively charged N-region with basic residues, central hydrophobic H-region of 7 to 15 leucine, valine, isoleucine residues forming alpha-helix, and C-region with polar residues and Ala-X-Ala motif for signal peptidase cleavage. Upon emergence from ribosome exit tunnel, hydrophobic core bound by 54 kDa subunit of signal recognition particle SRP that pauses translation and delivers ribosome-nascent chain complex to SRP receptor heterodimer at rough ER via GTP hydrolysis cycle, transferring chain to Sec61 translocon heterotrimer. Signal inserts into lateral gate opening channel, translocation proceeds cotranslationally into ER lumen or integration into membrane. Other signals include nuclear localization signal with lysine rich clusters, mitochondrial amphipathic helix, and peroxisomal SKL tripeptide, each ensuring accurate compartmentalization.
Ref: Blobel & Dobberstein, J Cell Biol 1975, Signal Hypothesis. Alberts 7th ed., Chapter 12, Targeting Signals.