Profiling the LAM Family of Contact Site Tethers Provides Insights into Their Regulation and Function

Emma J. Fenech; Meital Kupervaser; Angela Boshnakovska; Shani Ravid; Inês Gomes Castro; Yeynit Asraf; Sylvie Callegari; Christof Lenz; Henning Urlaub; Peter Rehling; Maya Schuldiner

doi:10.1177/25152564251321770

Profiling the LAM Family of Contact Site Tethers Provides Insights into Their Regulation and Function

Emma J. Fenech^*, Meital Kupervaser, Angela Boshnakovska, Shani Ravid, Inês Gomes Castro, Yeynit Asraf, Sylvie Callegari, Christof Lenz, Henning Urlaub, Peter Rehling, Maya Schuldiner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Membrane contact sites are molecular bridges between organelles that are sustained by tethering proteins and enable organelle communication. The endoplasmic reticulum (ER) membrane harbors many distinct families of tether proteins that enable the formation of contacts with all other organelles. One such example is the LAM (Lipid transfer protein Anchored at Membrane contact sites) family in yeast, which is composed of six members, each containing a putative lipid binding and transfer domain and an ER-embedded transmembrane segment. The family is divided into three homologous pairs each unique in their molecular architecture and localization to different ER subdomains. However, what determines the distinct localization of the different LAMs and which specific roles they carry out in each contact are still open questions. To address these, we utilized a labeling approach to profile the proximal protein landscape of the entire family. Focusing on unique, candidate interactors we could support that Lam5 resides at the ER-mitochondria contact site and demonstrate a role for it in sustaining mitochondrial activity. Capturing shared, putative interactors of multiple LAMs, we show how the Lam1/3 and Lam2/4 paralogous pairs could be associated specifically with the plasma membrane. Overall, our work provides new insights into the regulation and function of the LAM family members. More globally it demonstrates how proximity labeling can help identify the shared or unique functions of paralogous proteins.

Original language	English
Journal	Contact
Volume	8
DOIs	https://doi.org/10.1177/25152564251321770
Publication status	Published - 17 Apr 2025

Funding

We thank Dr. Ehud Sass, Sivan Arad and Noga Preminger from the Schuldiner lab for critical reading of this manuscript, and Reut Ester Avraham for making all the yeast media. We also thank: Dr Ofir Klein, Rosario Valenti and Noga Preminger for their technical support with experiments; Dr. Yury Bykov and Dr. Katja Hansen for their help and discussions on image analysis; Tanja Gall for her assistance with setting-up Seahorse assays; Corine Katina for helping with LC-MS/MS sample preparation; and Dr. Mike Tyler for his help with plotting heatmaps. GRAMD1A mass spectrometric experiments were supported by the University Medical Center Göttingen (UMG) Core Facility Proteomics. This project was supported by the Deutsche Forschungsgemeinschaft through the SFB1190 (P11, MS; P13, PR; Z02, HU). Emma Fenech was supported by a senior postdoctoral award from the Weizmann Institute of Science. Inês Gomes Castro is a recipient of an EMBO Long-term Fellowship (ALTF-580–2017). Maya Schuldiner is an incumbent of Dr. Gilbert Omenn and Martha Darling Professorial Chair in Molecular Genetics. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Deutsche Forschungsgemeinschaft, (grant number SFB1190).

All Science Journal Classification (ASJC) codes

Cell Biology
Physiology

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title = "Profiling the LAM Family of Contact Site Tethers Provides Insights into Their Regulation and Function",

abstract = "Membrane contact sites are molecular bridges between organelles that are sustained by tethering proteins and enable organelle communication. The endoplasmic reticulum (ER) membrane harbors many distinct families of tether proteins that enable the formation of contacts with all other organelles. One such example is the LAM (Lipid transfer protein Anchored at Membrane contact sites) family in yeast, which is composed of six members, each containing a putative lipid binding and transfer domain and an ER-embedded transmembrane segment. The family is divided into three homologous pairs each unique in their molecular architecture and localization to different ER subdomains. However, what determines the distinct localization of the different LAMs and which specific roles they carry out in each contact are still open questions. To address these, we utilized a labeling approach to profile the proximal protein landscape of the entire family. Focusing on unique, candidate interactors we could support that Lam5 resides at the ER-mitochondria contact site and demonstrate a role for it in sustaining mitochondrial activity. Capturing shared, putative interactors of multiple LAMs, we show how the Lam1/3 and Lam2/4 paralogous pairs could be associated specifically with the plasma membrane. Overall, our work provides new insights into the regulation and function of the LAM family members. More globally it demonstrates how proximity labeling can help identify the shared or unique functions of paralogous proteins.",

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AU - Fenech, Emma J.

AU - Kupervaser, Meital

AU - Boshnakovska, Angela

AU - Ravid, Shani

AU - Castro, Inês Gomes

AU - Asraf, Yeynit

AU - Callegari, Sylvie

AU - Lenz, Christof

AU - Urlaub, Henning

AU - Rehling, Peter

AU - Schuldiner, Maya

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N2 - Membrane contact sites are molecular bridges between organelles that are sustained by tethering proteins and enable organelle communication. The endoplasmic reticulum (ER) membrane harbors many distinct families of tether proteins that enable the formation of contacts with all other organelles. One such example is the LAM (Lipid transfer protein Anchored at Membrane contact sites) family in yeast, which is composed of six members, each containing a putative lipid binding and transfer domain and an ER-embedded transmembrane segment. The family is divided into three homologous pairs each unique in their molecular architecture and localization to different ER subdomains. However, what determines the distinct localization of the different LAMs and which specific roles they carry out in each contact are still open questions. To address these, we utilized a labeling approach to profile the proximal protein landscape of the entire family. Focusing on unique, candidate interactors we could support that Lam5 resides at the ER-mitochondria contact site and demonstrate a role for it in sustaining mitochondrial activity. Capturing shared, putative interactors of multiple LAMs, we show how the Lam1/3 and Lam2/4 paralogous pairs could be associated specifically with the plasma membrane. Overall, our work provides new insights into the regulation and function of the LAM family members. More globally it demonstrates how proximity labeling can help identify the shared or unique functions of paralogous proteins.

AB - Membrane contact sites are molecular bridges between organelles that are sustained by tethering proteins and enable organelle communication. The endoplasmic reticulum (ER) membrane harbors many distinct families of tether proteins that enable the formation of contacts with all other organelles. One such example is the LAM (Lipid transfer protein Anchored at Membrane contact sites) family in yeast, which is composed of six members, each containing a putative lipid binding and transfer domain and an ER-embedded transmembrane segment. The family is divided into three homologous pairs each unique in their molecular architecture and localization to different ER subdomains. However, what determines the distinct localization of the different LAMs and which specific roles they carry out in each contact are still open questions. To address these, we utilized a labeling approach to profile the proximal protein landscape of the entire family. Focusing on unique, candidate interactors we could support that Lam5 resides at the ER-mitochondria contact site and demonstrate a role for it in sustaining mitochondrial activity. Capturing shared, putative interactors of multiple LAMs, we show how the Lam1/3 and Lam2/4 paralogous pairs could be associated specifically with the plasma membrane. Overall, our work provides new insights into the regulation and function of the LAM family members. More globally it demonstrates how proximity labeling can help identify the shared or unique functions of paralogous proteins.

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Profiling the LAM Family of Contact Site Tethers Provides Insights into Their Regulation and Function

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