The human signal peptidase complex exists in two functional paralogs with distinct proteolytic subunits (SEC11A and SEC11C); the active site is formed by a catalytic triad abutting the ER membrane, where a transmembrane window thins the bilayer to generate specificity for signal peptides based on the length of their hydrophobic segments.

SEC11A is the catalytic subunit of SPC-A (with accessory subunits SPCS1, SPCS2, SPCS3); Ser-56 is the catalytic nucleophile and the C-terminal short (CTS) helix is essential for catalytic activity.

Beyond canonical N-terminal signal peptide removal, the human SPC (catalytic core SEC11A/C with SPCS3) cleaves misfolded or unassembled membrane proteins at otherwise hidden "cryptic" cleavage sites, which are abundant in the human membrane proteome; this post-translocational cleavage synergizes with ER-associated degradation (ERAD) to maintain membrane protein homeostasis.

Genome-wide CRISPR/Cas9 chemogenomic profiling in human cells and resistance selection in yeast identified the catalytic subunit of the signal peptidase (SEC11; human SEC11A and SEC11C) as the conserved efficacy target of cavinafungin, which rapidly blocks signal-sequence cleavage of host and viral proteins.

In yeast, the noncatalytic SPC subunit Spc2 (ortholog of human SPCS2) modulates SPC discrimination between substrates and cleavage-site selection; molecular dynamics indicates Spc2 contributes to the membrane thinning at the center of the SPC that underlies substrate recognition, informing the conserved mechanism by which accessory subunits support the SEC11 catalytic subunit.

A non-cleavable variant preprotein (proline introduced immediately after the signal-peptide cleavage site, e.g. preproinsulin pPI-F25P) is translocated across the ER membrane where it binds the catalytic SPase subunit SEC11A and inhibits signal peptidase activity in a dose-dependent manner, impairing in trans the processing/maturation of co-expressed preproteins and of viral polypeptides; this identifies eukaryotic SPase (human SEC11A) as a tractable therapeutic/antiviral target.

In locally advanced gastric cancer (n=253), high SEC11A mRNA expression was associated with worse 5-year overall survival and was an independent predictor of poor prognosis in multivariate analysis.

In TCGA head and neck squamous cell carcinoma, SEC11A was upregulated in tumors versus adjacent normal tissue and higher SEC11A expression independently predicted poorer progression-free and disease-specific survival; expression correlated with SEC11A copy number.

SEC11A is the catalytic subunit of the signal peptidase complex paralog A (SPC-A) with SPCS1/2/3; cleaves N-terminal signal peptides (EC 3.4.21.89) from nascent proteins translocated into the ER lumen; single-pass type II ER membrane protein; peptidase S26B family; catalytic triad (Ser-56), selectivity for h-regions shorter than 18-20 residues via membrane thinning.