Signal peptidase complexes set species-specific rules for signal peptide cleavage
Abstract
Protein secretion is essential for cell function and begins when signal peptides direct nascent proteins into the secretory pathway, where they are cleaved by the signal peptidase complex (SPC). Although this pathway is highly conserved, signal peptides do not always function efficiently across species, and the molecular basis for this incompatibility remains unclear. Here, we show that human signal peptides with longer hydrophobic cores efficiently target and translocate nascent proteins in both yeast and human but are frequently left uncleaved in yeast, identifying signal peptide cleavage as a major barrier to cross-species compatibility. Molecular dynamics (MD) simulations reveal that, despite their highly conserved architectures, yeast and human SPCs generate distinct membrane-thinning profiles near the signal peptide-binding region. Our results support a model in which SPC–lipid interactions tune the local membrane environment to accommodate signal peptides of distinct hydrophobic core length, providing a biophysical mechanism for species-specific signal peptide recognition. These findings offer a mechanistic framework for understanding and potentially engineering protein secretion across diverse expression hosts.
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BibTeX
@misc{chung2026signal,
title = {{Signal peptidase complexes set species-specific rules for signal peptide cleavage}},
author = {Yeonji Chung and Gilberto P Pereira and Young June Lee and Achille Agnesa and Lisbeth R Kjølbye and Henrik Nielsen and Gunnar von Heijne and Paulo C T Souza and Hyun Kim},
howpublished = {HAL},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.752496},
url = {https://hal.science/hal-05787660v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Signal peptidase complexes set species-specific rules for signal peptide cleavage
AU - Yeonji Chung
AU - Gilberto P Pereira
AU - Young June Lee
AU - Achille Agnesa
AU - Lisbeth R Kjølbye
AU - Henrik Nielsen
AU - Gunnar von Heijne
AU - Paulo C T Souza
AU - Hyun Kim
PY - 2026
DA - 2026/09/20
PB - HAL
DO - 10.64898/2026.09.20.752496
UR - https://hal.science/hal-05787660v1
AB - Protein secretion is essential for cell function and begins when signal peptides direct nascent proteins into the secretory pathway, where they are cleaved by the signal peptidase complex (SPC). Although this pathway is highly conserved, signal peptides do not always function efficiently across species, and the molecular basis for this incompatibility remains unclear. Here, we show that human signal peptides with longer hydrophobic cores efficiently target and translocate nascent proteins in both yeast and human but are frequently left uncleaved in yeast, identifying signal peptide cleavage as a major barrier to cross-species compatibility. Molecular dynamics (MD) simulations reveal that, despite their highly conserved architectures, yeast and human SPCs generate distinct membrane-thinning profiles near the signal peptide-binding region. Our results support a model in which SPC–lipid interactions tune the local membrane environment to accommodate signal peptides of distinct hydrophobic core length, providing a biophysical mechanism for species-specific signal peptide recognition. These findings offer a mechanistic framework for understanding and potentially engineering protein secretion across diverse expression hosts.
ER -