Summary
One-third of eukaryotic genes encode for integral membrane proteins (IMPs) with the majority being assembled at the endoplasmic reticulum (ER) after being translated by the ribosome. The SRP-independent (SND) targeting pathway was recently identified as a new route for ER targeting and insertion of IMPs. It was found to recognise a subset of IMPs with a central transmembrane domain, yet it also serves as an alternative route to deliver a broad range of substrates to the ER when their canonical pathways are impaired. The yeast SND pathway comprises three components, SND1, SND2 and SND3. The cytosolic SND1 is a putative ribosome-associated factor and receptor for nascent IMP substrates. SND2 and SND3 are proposed to form a heterodimeric complex at the ER membrane that, together with the SEC61 translocon, mediates membrane insertion of substrates. However, direct evidence for the roles of the SND components and their physical interactions with each other and complexes such as the ribosome and the SEC61 translocon is lacking.
This project aims to elucidate the molecular interplays between SND components and other targeting and insertion factors using a combination of structural biology, biophysics, and biochemistry. First, I will establish a genomic tagging system to purify SND complexes from Chaetomium thermophilum. I will integrate mass spectrometry and different biophysical tools to identify and subsequently characterise the interactions between SND components and their associated proteins involved in ER membrane targeting and insertion, or potentially other novel biological functions. Ultimately, I will solve the structures of endogenous SND complexes by cryo-electron microscopy. This work will provide comprehensive insights into how the SND complexes capture a broad range of substrates and execute their ER membrane targeting and insertion, and will thus have far-reaching impacts on our current understanding of membrane protein biology.
This project aims to elucidate the molecular interplays between SND components and other targeting and insertion factors using a combination of structural biology, biophysics, and biochemistry. First, I will establish a genomic tagging system to purify SND complexes from Chaetomium thermophilum. I will integrate mass spectrometry and different biophysical tools to identify and subsequently characterise the interactions between SND components and their associated proteins involved in ER membrane targeting and insertion, or potentially other novel biological functions. Ultimately, I will solve the structures of endogenous SND complexes by cryo-electron microscopy. This work will provide comprehensive insights into how the SND complexes capture a broad range of substrates and execute their ER membrane targeting and insertion, and will thus have far-reaching impacts on our current understanding of membrane protein biology.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101107937 |
| Start date: | 01-06-2023 |
| End date: | 31-05-2025 |
| Total budget - Public funding: | - 189 687,00 Euro |
Cordis data
Original description
One-third of eukaryotic genes encode for integral membrane proteins (IMPs) with the majority being assembled at the endoplasmic reticulum (ER) after being translated by the ribosome. The SRP-independent (SND) targeting pathway was recently identified as a new route for ER targeting and insertion of IMPs. It was found to recognise a subset of IMPs with a central transmembrane domain, yet it also serves as an alternative route to deliver a broad range of substrates to the ER when their canonical pathways are impaired. The yeast SND pathway comprises three components, SND1, SND2 and SND3. The cytosolic SND1 is a putative ribosome-associated factor and receptor for nascent IMP substrates. SND2 and SND3 are proposed to form a heterodimeric complex at the ER membrane that, together with the SEC61 translocon, mediates membrane insertion of substrates. However, direct evidence for the roles of the SND components and their physical interactions with each other and complexes such as the ribosome and the SEC61 translocon is lacking.This project aims to elucidate the molecular interplays between SND components and other targeting and insertion factors using a combination of structural biology, biophysics, and biochemistry. First, I will establish a genomic tagging system to purify SND complexes from Chaetomium thermophilum. I will integrate mass spectrometry and different biophysical tools to identify and subsequently characterise the interactions between SND components and their associated proteins involved in ER membrane targeting and insertion, or potentially other novel biological functions. Ultimately, I will solve the structures of endogenous SND complexes by cryo-electron microscopy. This work will provide comprehensive insights into how the SND complexes capture a broad range of substrates and execute their ER membrane targeting and insertion, and will thus have far-reaching impacts on our current understanding of membrane protein biology.
Status
SIGNEDCall topic
HORIZON-MSCA-2022-PF-01-01Update Date
31-07-2023
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