Structural basis of signal peptide recognition by the signal peptidase complex
Abstract
The signal peptidase complex (SPC) is responsible for cleaving signal peptides (SPs) from approximately 10% of the human proteome. SPs are characterized by a tripartite structure, consisting of an N-terminal n-region, a central helical h-region and a C-terminal c-region, each defined by rather general chemical properties rather than strict sequence conservation. Despite their sequence diversity, SPC recognizes and processes SPs with exquisite specificity. Here, we present a 2.6 Å cryo-EM map of the human SPC-A, one of two SPC paralogs, bound to a model SP. The c-region binds to a hydrophobic binding groove near the active site, a narrow gate marks the transition from c- to h-region, and the h-region localizes in a transmembrane (TM) window. Substrate engagement stabilizes N- and C-terminal helices of Sec11A, which frame the SP and are unresolved in the apo structure. Molecular dynamics (MD) simulations confirm a stable hydrogen-bonding network at the c-region and indicate dynamic interactions within a thinned lipid environment at the TM window. AlphaFold modeling supports this binding mode across physiological SPs. Collectively, our structural and computational analyses explain how the SPC achieves its specificity by combining the selectivity of the luminal binding groove and of the transmembrane window.
Related
- Signal peptidase complexes set species-specific rules for signal peptide cleavage
- The Sec11 C-terminal short helix promotes productive engagement of internal signal sequences with the signal peptidase complex
- Structural basis of nucleosome recognition by the human NuA4/TIP60 acetyltransferase complex
- Sample preparation for direct nanopore based protein identification via tryptic peptide recognition
- Sec Signal Peptide Doubles Up as a Leader Sequence in Bufferin Biosynthesis
BibTeX
@article{liaci2026structural,
title = {{Structural basis of signal peptide recognition by the signal peptidase complex}},
author = {A Manuel Liaci and Dimitrios Vismpas and Lisbeth R Kjølbye and Ioannis Skalidis and Gilberto P Pereira and Adrian Fujiet Koh and Mariska Gröllers-Mulderij and Abhay Kotecha and Paulo C. T. Souza and Friedrich Förster},
journal = {Nature Communications},
year = {2026},
month = may,
doi = {10.1038/s41467-026-73423-3},
url = {https://hal.science/hal-05792195v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Structural basis of signal peptide recognition by the signal peptidase complex
AU - A Manuel Liaci
AU - Dimitrios Vismpas
AU - Lisbeth R Kjølbye
AU - Ioannis Skalidis
AU - Gilberto P Pereira
AU - Adrian Fujiet Koh
AU - Mariska Gröllers-Mulderij
AU - Abhay Kotecha
AU - Paulo C. T. Souza
AU - Friedrich Förster
PY - 2026
DA - 2026/05/22
JO - Nature Communications
DO - 10.1038/s41467-026-73423-3
UR - https://hal.science/hal-05792195v1
AB - The signal peptidase complex (SPC) is responsible for cleaving signal peptides (SPs) from approximately 10% of the human proteome. SPs are characterized by a tripartite structure, consisting of an N-terminal n-region, a central helical h-region and a C-terminal c-region, each defined by rather general chemical properties rather than strict sequence conservation. Despite their sequence diversity, SPC recognizes and processes SPs with exquisite specificity. Here, we present a 2.6 Å cryo-EM map of the human SPC-A, one of two SPC paralogs, bound to a model SP. The c-region binds to a hydrophobic binding groove near the active site, a narrow gate marks the transition from c- to h-region, and the h-region localizes in a transmembrane (TM) window. Substrate engagement stabilizes N- and C-terminal helices of Sec11A, which frame the SP and are unresolved in the apo structure. Molecular dynamics (MD) simulations confirm a stable hydrogen-bonding network at the c-region and indicate dynamic interactions within a thinned lipid environment at the TM window. AlphaFold modeling supports this binding mode across physiological SPs. Collectively, our structural and computational analyses explain how the SPC achieves its specificity by combining the selectivity of the luminal binding groove and of the transmembrane window.
SN - 2041-1723
SN - 2041-1723
ER -