Consensus N-terminal Secretory Signal Peptide

N-terminal signal peptides (15–30 aa) directing newly synthesized proteins co-translationally to the ER lumen for secretion or membrane integration. Tripartite structure with a positively charged n-region, hydrophobic core, and signal peptidase cleavage site ensures >95% ER targeting efficiency. IgK leader and IL-2 signal peptide are the standard choices for secreted therapeutic payloads in AAV gene therapy vectors.

Length: 60 bp

Subtype: Signal peptide

Target: Secreted

Efficiency: Typically >95% ER targeting; cleavage varies by sequence and context

Origin: Various mammalian secretory proteins (IgK, IL-2, albumin, etc.)

Characteristics

Tripartite structure: positively charged n-region, hydrophobic h-region (~10 aa), c-region with signal peptidase cleavage site (A-X-A motif). Cleaved co-translationally by signal peptidase in ER lumen. Cargo ends up secreted or membrane-integrated depending on downstream sequences.

Applications: Directing antibody chains, cytokines, growth factors, and secreted reporters to the secretory pathway. Required for all ER-targeted proteins. Used in AAV-delivered secreted therapeutic payloads.

Limitations: Signal peptide efficiency is context-dependent—the downstream protein sequence can affect cleavage efficiency and targeting. Not all signal peptides work equally well for all cargo. IgK leader is generally preferred for antibody applications; species-matched signals preferred for expression in specific cell types.

References

  1. von Heijne et al. (1990). The signal peptide. J Membr Biol - vonHeijne 1990 Signal Peptides