High-throughput affinity-purification interactome of SARS-CoV-2 and human coronavirus proteins; source of the IntAct SPCS2-spike (S) interaction.

Cryo-EM structures of the two human SPC paralogs identify SPCS2 as an accessory subunit; the complex forms a transmembrane window that locally thins the ER bilayer, generating specificity for signal-peptide hydrophobic-segment length.

In yeast, depletion or mutation of Spc2 (ortholog of human SPCS2) compromises the SPC's ability to discriminate between substrates and to identify the correct cleavage site; molecular dynamics simulations show that membrane thinning at the center of the SPC is reduced without Spc2, providing a molecular explanation for the altered substrate-recognition properties.

The C-terminal region of the tail-anchored ER protein Jaw1 (IRAG2/LRMP) is cleaved after insertion specifically by the SEC11A-containing (but not SEC11C-containing) signal peptidase complex; this noncanonical post-insertional cleavage enhances Jaw1's augmentative effect on IP3 receptor-mediated Ca2+ release, linking SPC (of which SPCS2 is an accessory subunit) to ER Ca2+ signaling.

An affinity-purification mass-spectrometry interactome of HCV-infected cells found that cell-derived SPCS2 interacts with both HCV p7 and E2, implicating the SPCS2-containing SPC in HCV glycoprotein/viroporin processing at the assembly stage.

Non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A with SEC11A and SPC-C with SEC11C, each also containing SPCS1 and SPCS3); multi-pass ER membrane protein; enhances SPC enzymatic activity and facilitates translocation-site component interactions.