Short hydrophobic sequences block secretory proteins from entering the Endoplasmic Reticulum

Alexandra Schatt; Thomas Martinetz; Enno Hartmann; Kai-Uwe Kalies

Short hydrophobic sequences block secretory proteins from entering the Endoplasmic Reticulum

Alexandra Schatt, Thomas Martinetz, Enno Hartmann, Kai-Uwe Kalies

Abstract

Approximately one-third of all mammalian proteins enter the secretory pathway via the endoplasmic reticulum (ER). For most of these proteins,
ER entry is mediated by the Sec61 translocon and initiated by N-terminal signal sequences that promote protein import. How Sec61 accommodates diverse signal sequences while preventing mistargeting of cytosolic proteins remains poorly understood.
Here, we identify short hydrophobic segments as intrinsic negative regulators of ER import. Bioinformatic analyses revealed that clusters of hydrophobic amino acids are enriched in cytosolic proteins but rare in secretory proteins. Using model substrates, we show that such segments can inhibit ER translocation despite the presence of a functional signal sequence. Translocation stalls at the hydrophobic segment, leading to
release of the protein back into the cytosol. Our findings uncover a previously unrecognized mechanism that counteracts ER import and
enhances protein-sorting fidelity by preventing the mislocalization of cytosolic proteins to the ER.

Originalsprache	Englisch
Publikationsstatus	Veröffentlicht - 21.09.2026
Veranstaltung	Advances and new frontiers in protein translocation across membranes - Sant Feliu de Guíxols, Spanien Dauer: 21.09.2026 → 25.09.2026

Tagung, Konferenz, Kongress

Tagung, Konferenz, Kongress	Advances and new frontiers in protein translocation across membranes
Land/Gebiet	Spanien
Zeitraum	21.09.26 → 25.09.26

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Zitieren

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title = "Short hydrophobic sequences block secretory proteins from entering the Endoplasmic Reticulum",

abstract = "Approximately one-third of all mammalian proteins enter the secretory pathway via the endoplasmic reticulum (ER). For most of these proteins, ER entry is mediated by the Sec61 translocon and initiated by N-terminal signal sequences that promote protein import. How Sec61 accommodates diverse signal sequences while preventing mistargeting of cytosolic proteins remains poorly understood. Here, we identify short hydrophobic segments as intrinsic negative regulators of ER import. Bioinformatic analyses revealed that clusters of hydrophobic amino acids are enriched in cytosolic proteins but rare in secretory proteins. Using model substrates, we show that such segments can inhibit ER translocation despite the presence of a functional signal sequence. Translocation stalls at the hydrophobic segment, leading to release of the protein back into the cytosol. Our findings uncover a previously unrecognized mechanism that counteracts ER import and enhances protein-sorting fidelity by preventing the mislocalization of cytosolic proteins to the ER.",

author = "Alexandra Schatt and Thomas Martinetz and Enno Hartmann and Kai-Uwe Kalies",

year = "2026",

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language = "English",

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TY - CONF

T1 - Short hydrophobic sequences block secretory proteins from entering the Endoplasmic Reticulum

AU - Schatt, Alexandra

AU - Martinetz, Thomas

AU - Hartmann, Enno

AU - Kalies, Kai-Uwe

PY - 2026/9/21

Y1 - 2026/9/21

N2 - Approximately one-third of all mammalian proteins enter the secretory pathway via the endoplasmic reticulum (ER). For most of these proteins, ER entry is mediated by the Sec61 translocon and initiated by N-terminal signal sequences that promote protein import. How Sec61 accommodates diverse signal sequences while preventing mistargeting of cytosolic proteins remains poorly understood. Here, we identify short hydrophobic segments as intrinsic negative regulators of ER import. Bioinformatic analyses revealed that clusters of hydrophobic amino acids are enriched in cytosolic proteins but rare in secretory proteins. Using model substrates, we show that such segments can inhibit ER translocation despite the presence of a functional signal sequence. Translocation stalls at the hydrophobic segment, leading to release of the protein back into the cytosol. Our findings uncover a previously unrecognized mechanism that counteracts ER import and enhances protein-sorting fidelity by preventing the mislocalization of cytosolic proteins to the ER.

AB - Approximately one-third of all mammalian proteins enter the secretory pathway via the endoplasmic reticulum (ER). For most of these proteins, ER entry is mediated by the Sec61 translocon and initiated by N-terminal signal sequences that promote protein import. How Sec61 accommodates diverse signal sequences while preventing mistargeting of cytosolic proteins remains poorly understood. Here, we identify short hydrophobic segments as intrinsic negative regulators of ER import. Bioinformatic analyses revealed that clusters of hydrophobic amino acids are enriched in cytosolic proteins but rare in secretory proteins. Using model substrates, we show that such segments can inhibit ER translocation despite the presence of a functional signal sequence. Translocation stalls at the hydrophobic segment, leading to release of the protein back into the cytosol. Our findings uncover a previously unrecognized mechanism that counteracts ER import and enhances protein-sorting fidelity by preventing the mislocalization of cytosolic proteins to the ER.

M3 - Poster

T2 - Advances and new frontiers in protein translocation across membranes

Y2 - 21 September 2026 through 25 September 2026

ER -