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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)3934-3948.e11
Number of pages15
JournalMolecular Cell
Volume81
Issue number19
Early online date12-Aug-2021
DOIs
Publication statusPublished - 7-Oct-2021

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