What happens to the precursor protein's signal sequence after it is cleaved?
After cleavage, the signal sequence is generally thought to be degraded by intramembrane proteases (since it is embedded in the endoplasmic reticulum membrane). For at least some proteins, the signal sequence is further processed and released into the cytoplasm or ER lumen. 

Martoglio B. 2003. Intramembrane proteolysis and post-targeting functions of signal peptides. Biochem Soc Trans 31:1243-1247


  When translocation continues, the signal sequence’s c-region appears in the ER lumen and becomes accessible to signal peptidase, which cleaves the signal sequence from the pre-protein. The latter is further translocated into the ER lumen, while the liberated signal peptide is usually not detected in assay systems, implying rapid degradation. In a cell-free in vitro system with ER membranes from canine pancreas, we reported several years ago that after cleavage by signal peptidase, the liberated signal peptide is transiently embedded in the lipid bilayer and undergoes further processing to be released from the membrane. 




The activity of released signal sequences is not entirely known and only partially characterized for some proteins. The following review discusses some functions of signal peptides after cleavage:

Martoglio B, Dobberstein B. 1998. Signal sequences: more than just greasy peptides. Trends Cell Bio 8(10):410-415

The signal peptide of bovine preprolactin and HIV gp160 can bind calmodulin.


  …the signal sequence of bovine preprolactin, which consists of 30 amino acid residues, is cleaved by signal peptidase and then further processed by an unknown signal peptide peptidase (SPPase; Fig. 4) … This signal peptide fragment resides initially in the membrane and, after a chase period, is released into the cytosol. Once in the cytosol, the signal peptide fragment binds to calmodulin in a Ca2+-dependent manner. A signal peptide fragment derived from HIV-1 gp160 also binds to calmodulin when it is released into the cytosol … With their n-regions having the potential to form a basic amphiphilic α-helix and their hydrophobic C-terminal region, they are similar to other calmodulin-binding domains. Calmodulin is a small, acidic protein involved in the regulation of many cellular processes controlled by Ca2+-dependent signalling pathways. It is possible that binding of signal peptide fragments to calmodulin influences Ca2+/calmodulin-dependent cellular signal-transduction pathways. Further studies are required to elucidate the physiological consequences of interactions between signal peptide fragments and calmodulin.


The signal peptides of MHC class I proteins are presented to NK cells by MHC-I (with HLA-E alpha chain). This allows monitoring of MHC-I expression, which is often disrupted in virally infected or cancerous cells.


  Peptides presented by classical MHC class I molecules represent the broad spectrum of peptides generated by the proteasome. In contrast to this general use of peptides, only a very specific signal peptide fragment is presented by so-called nonclassical MHC class I molecules (HLA-E in human). These molecules monitor the presence of classical MHC class I molecules by presenting a signal peptide fragment derived from HLA-A, -B or -C to natural killer (NK) cells (Fig. 5b). NK cells destroy cells unable to activate inhibitory receptors specific for MHC class I molecules. 




This book section discusses the function of signal peptides in some viruses:

Kapp K, Schrempf S, Lemberg MK, Dobberstein B. 2009. Post-targeting functions of signal peptides. In: Protein Transport into the Endoplasmic Reticulum, Zimmermann R.