2. Academic Validation
  3. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage

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

  • Mol Cell. 2021 Oct 7;81(19):3934-3948.e11. doi: 10.1016/j.molcel.2021.07.031.
A Manuel Liaci 1,  Barbara Steigenberger 2,  Paulo Cesar Telles de Souza 3,  Sem Tamara 2,  Mariska Gröllers-Mulderij 1,  Patrick Ogrissek 4,  Siewert J Marrink 5,  Richard A Scheltema 2,  Friedrich Förster 6
Affiliations

Affiliations

  • 1 Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands.
  • 2 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, the Netherlands.
  • 3 Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Material, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands; Molecular Microbiology and Structural Biochemistry, UMR 5086, CNRS and University of Lyon, Lyon, France.
  • 4 Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands; Institute of Chemistry and Metabolomics, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
  • 5 Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Material, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands.
  • 6 Structural Biochemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands. Electronic address: f.g.forster@uu.nl.
PMID: 34388369 DOI: 10.1016/j.molcel.2021.07.031
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.

Keywords

ER translocon; crosslinking mass spectrometry; cryo-EM; membrane thinning; molecular dynamics simulations; protein maturation; protein secretion; secretory pathway; signal peptidase complex; signal peptide.

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