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Assembly and fission of tubular carriers mediating protein sorting in endosomes

Abstract

Endosomes are central protein-sorting stations at the crossroads of numerous membrane trafficking pathways in all eukaryotes. They have a key role in protein homeostasis and cellular signalling and are involved in the pathogenesis of numerous diseases. Endosome-associated protein assemblies or coats collect transmembrane cargo proteins and concentrate them into retrieval domains. These domains can extend into tubular carriers, which then pinch off from the endosomal membrane and deliver the cargoes to appropriate subcellular compartments. Here we discuss novel insights into the structure of a number of tubular membrane coats that mediate the recruitment of cargoes into these carriers, focusing on sorting nexin-based coats such as Retromer, Commander and ESCPE-1. We summarize current and emerging views of how selective tubular endosomal carriers form and detach from endosomes by fission, highlighting structural aspects, conceptual challenges and open questions.

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Fig. 1: Major endosomal trafficking pathways in yeast and mammalian cells.
Fig. 2: Domain organization and lipid-binding properties of SNX proteins.
Fig. 3: Structures of endosomal coat complexes.
Fig. 4: Arrangements of SNX–Retromer coats.
Fig. 5: Formation of a tubular endosomal carrier.
Fig. 6: Factors and mechanisms that can promote carrier detachment.

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Acknowledgements

This work was supported by grants from the Swiss National Science Foundation (179306 and 204713) to A.M. B.C. is supported by an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (APP2016410).

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A.M. and N.G. researched data for the article. All authors contributed equally to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Navin Gopaldass or Andreas Mayer.

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Glossary

Coarse-grained molecular dynamics simulations

A technique to calculate the interaction and dynamics of molecular systems, in which the participating molecules are represented in a simplified, cruder representation (for example, a bead representing an entire functional group). This coarse-grained representation facilitates calculation of the dynamic changes in the system.

Coincidence detection

Combination of several molecular interactions to trigger an event such as membrane recruitment and coat formation.

Cryo-electron microscopy

An electron microscopy technique in which samples are imaged in the frozen state, usually without fixation. Extremely rapid freezing of the samples circumvents the formation of ice crystals and facilitates high-resolution analysis of the structures of proteins and membranes

Cryo-electron tomography

(CryoET). A cryo-electron microscopy approach in which a sample is imaged under different tilt angles. High-resolution structural information can be calculated from the image series.

Giant unilamellar liposomes

Very large (typically 10–50 µm diameter) synthetic lipid vesicles. They are well suited to analyse changes in their membrane shape by light microscopy.

Line tension

In the context of membranes, this describes the interfacial energy at the boundary of membrane domains (regions of differing lipid and/or protein composition) that forces the membrane to minimize this domain boundary.

Melanosomes

Lysosome-related organelles that produce and accumulate melanin. They differentiate out of endosomes and form tubulo-vesicular carriers during this maturation process.

Replicative niche

An intracellular space that is exploited by pathogens to grow and proliferate inside a host cell.

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Gopaldass, N., Chen, KE., Collins, B. et al. Assembly and fission of tubular carriers mediating protein sorting in endosomes. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00746-8

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