Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage

Journal article
Proteins
Lipid membranes
Author

A. Manuel Liaci, Barbara Steigenberger, Paulo Cesar Telles de Souza, Sem Tamara, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert J. Marrink, Richard A. Scheltema and Friedrich Förster

Doi

https://doi.org/10.1016/j.molcel.2021.07.031

Citation (APA 7)

Liaci, A. M., Steigenberger, B., de Souza, P. C. T., Tamara, S., Gröllers-Mulderij, M., Ogrissek, P., … & Förster, F. (2021). Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Molecular cell, 81(19), 3934-3948.

Abstract

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. Molecular dynamics simulations indicate that this unique architecture generates specificity for SPs based on the length of their hydrophobic segments.