ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

Koch, Christian; Schuldiner, Maya; Herrmann, Johannes M.

doi:10.3390/ijms22179655

Cited by 24 publications

(28 citation statements)

References 120 publications

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“…With the exception of resident proteins of the ER, most of the correctly folded and assembled proteins are transported to their functional location by trafficking vesicles, which bud from sub-domains of the tubular ER that are termed exit sites (ERES) ( Raote et al, 2018 ; Raote et al, 2020 ) . In recent years, however, an increasing number of membrane proteins destined to lipid droplets, peroxisomes or mitochondria was observed to be first targeted to and inserted into the ER membrane prior to their integration into budding lipid droplets or peroxisomes or prior to their delivery to mitochondria via the ER-SURF pathway ( Hansen et al, 2018 ; Schrul and Schliebs, 2018 ; Jansen and Klei, 2019 ; Dhimann et al, 2020 ; Goodman, 2020 ; Koch et al, 2021 ; Lalier et al, 2021 ). Interestingly, the budding of lipid droplets and peroxisomes also occurs in sub-domains of the tubular ER, which may be spatially or physically related to ERES (see below) ( Schrul and Kopito, 2016 ; Song et al, 2021 ; Zimmermann et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Signal Peptide Features Determining the Substrate Specificities of Targeting and Translocation Components in Human ER Protein Import

et al. 2022

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In human cells, approximately 30% of all polypeptides enter the secretory pathway at the level of the endoplasmic reticulum (ER). This process involves cleavable amino-terminal signal peptides (SPs) or more or less amino-terminal transmembrane helices (TMHs), which serve as targeting determinants, at the level of the precursor polypeptides and a multitude of cytosolic and ER proteins, which facilitate their ER import. Alone or in combination SPs and TMHs guarantee the initial ER targeting as well as the subsequent membrane integration or translocation. Cytosolic SRP and SR, its receptor in the ER membrane, mediate cotranslational targeting of most nascent precursor polypeptide chains to the polypeptide-conducting Sec61 complex in the ER membrane. Alternatively, fully-synthesized precursor polypeptides and certain nascent precursor polypeptides are targeted to the ER membrane by either the PEX-, SND-, or TRC-pathway. Although these targeting pathways may have overlapping functions, the question arises how relevant this is under cellular conditions and which features of SPs and precursor polypeptides determine preference for a certain pathway. Irrespective of their targeting pathway(s), most precursor polypeptides are integrated into or translocated across the ER membrane via the Sec61 channel. For some precursor polypeptides specific Sec61 interaction partners have to support the gating of the channel to the open state, again raising the question why and when this is the case. Recent progress shed light on the client spectrum and specificities of some auxiliary components, including Sec62/Sec63, TRAM1 protein, and TRAP. To address the question which precursors use a certain pathway or component in intact human cells, i.e., under conditions of fast translation rates and molecular crowding, in the presence of competing precursors, different targeting organelles, and relevant stoichiometries of the involved components, siRNA-mediated depletion of single targeting or transport components in HeLa cells was combined with label-free quantitative proteomics and differential protein abundance analysis. Here, we present a summary of the experimental approach as well as the resulting differential protein abundance analyses and discuss their mechanistic implications in light of the available structural data.

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Section: Introductionmentioning

confidence: 99%

Signal Peptide Features Determining the Substrate Specificities of Targeting and Translocation Components in Human ER Protein Import

et al. 2022

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“…One such protein, Tim21 is a mitochondrial inner membrane protein that both interacts with Ssh1 and is affected by its loss. Tim21 is a typical substrate of the ER-SURF pathway in which mitochondrial inner membrane proteins utilize the ER surface to target to mitochondria (Hansen et al, 2018; Koch et al, 2021). Indeed, strains deleted for SSH1 have previously been shown to have respiratory effects, enhanced DNA loss (Wilkinson et al, 2001) as well as altered mitochondrial biogenesis (Laborenz et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

A systematic approach to study protein-substrate specificity enables the identification of Ssh1 substrate range

Cohen

Aviram

Schuldiner

2022

Preprint

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Many cellular functions are carried out by protein pairs, or families, providing robustness alongside functional diversity. For such processes, it remains a challenge to map the degree of specificity versus promiscuity. Protein-protein interactions (PPIs) can be used to inform on these matters as they highlight cellular locals, regulation and, in cases where proteins affect other proteins - substrate range. However, methods to study transient PPIs systematically are underutilized. In this study we create a novel approach to study stable as well as transient PPIs in yeast. Our approach, Cel-lctiv (CELlular biotin-Ligation for Capturing Transient Interactions in Vivo), uses high- throughput pairwise proximity biotin ligation for uncovering PPIs systematically and in vivo. As a proof of concept we study the homologous translocation pores Sec61 and Ssh1. We show how Cel-lctiv can uncover the unique substrate range for each translocon allowing us to pinpoint a specificity determinator driving interaction preference. More generally this demonstrates how CEl-lctiv can provide direct information on substrate specificity even for highly homologous proteins.

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“…Despite all control, mistargeting may occur, for which separate regulation systems have been established by the cell, such as for the removal of proteins from the mitochondrial outer membrane or ER membrane [ 213 , 214 ]. Moreover, the dual targeting, re-targeting, or SURFing of proteins from one organelle to another potentiate the diversity of targeting networks [ 153 , 215 , 216 ].…”

Section: Multifactorial Polypeptide Targeting Pathways: the Srp Get And Snd Systemsmentioning

confidence: 99%

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

Tirincsi

Sicking

Hadzibeganovic

et al. 2021

IJMS

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Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades taught us one humble lesson: no one size fits all. Cells use an impressive array of components to enable the safe transport of protein cargo from the cytosolic ribosomes to the endoplasmic reticulum. Safety during the transit is warranted by the interplay of cytosolic chaperones, membrane receptors, and protein translocases that together form functional networks and serve as protein targeting and translocation routes. While two targeting routes to the endoplasmic reticulum, SRP (signal recognition particle) and GET (guided entry of tail-anchored proteins), prefer targeting determinants at the N- and C-terminus of the cargo polypeptide, respectively, the recently discovered SND (SRP-independent) route seems to preferentially cater for cargos with non-generic targeting signals that are less hydrophobic or more distant from the termini. With an emphasis on targeting routes and protein translocases, we will discuss those functional networks that drive efficient protein topogenesis and shed light on their redundant and dynamic nature in health and disease.

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ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

Cited by 24 publications

References 120 publications

Signal Peptide Features Determining the Substrate Specificities of Targeting and Translocation Components in Human ER Protein Import

Signal Peptide Features Determining the Substrate Specificities of Targeting and Translocation Components in Human ER Protein Import

A systematic approach to study protein-substrate specificity enables the identification of Ssh1 substrate range

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

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