PT  - JOURNAL ARTICLE
AU  - A. Manuel Liaci
AU  - Barbara Steigenberger
AU  - Sem Tamara
AU  - Paulo Cesar Telles de Souza
AU  - Mariska Gröllers-Mulderij
AU  - Patrick Ogrissek
AU  - Siewert J. Marrink
AU  - Richard A. Scheltema
AU  - Friedrich Förster
TI  - Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage
AID  - 10.1101/2020.11.11.378711
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.11.378711
4099  - http://biorxiv.org/content/early/2020/11/11/2020.11.11.378711.short
4100  - http://biorxiv.org/content/early/2020/11/11/2020.11.11.378711.full
AB  - The signal peptidase complex (SPC) is an essential membrane complex in the endoplasmic reticulum (ER), where it removes signal peptides (SPs) from a large variety of secretory pre-proteins with exquisite specificity. Although the determinants of this process have been established empirically, the molecular details of SP recognition and removal remain elusive. Here, we show that the human SPC exists in two functional paralogs with distinct proteolytic subunits. We determined the atomic structures of both paralogs using electron cryo-microscopy and structural proteomics. The active site is formed by a catalytic triad and abuts the ER membrane, where a transmembrane window collectively formed by all subunits locally thins the bilayer. This unique architecture generates specificity for thousands of SPs based on the length of their hydrophobic segments.Competing Interest StatementThe authors have declared no competing interest.