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A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer

Gallon, Matthew, Clairfeuille, Thomas, Steinberg, Florian, Mas, Caroline, Ghai, Rajesh, Sessions, Richard B., Teasdale, Rohan D., Collins, Brett M., Cullen, Peter J.·2014·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1410552111
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Abstract

Significance: Cell surface proteins are regulated by a constant cycle of internalization and recycling from intracellular compartments called endosomes. From these organelles, two protein sorting platforms, sorting nexin 27 (SNX27) and the retromer complex, play a critical role in the retrieval of various proteins responsible for ion transport, glucose metabolism, neurotransmission, and other cell functions. Based on the three-dimensional structure of SNX27 in complex with the retromer subunit VPS26, we define the mechanism by which these proteins cooperate to drive endosomal cargo sorting. Retromer and SNX27 dysfunction is implicated in various disorders, including diabetes, Down syndrome, Parkinson disease, and Alzheimer’s disease, and this work provides important insights into the assembly of this essential endosomal sorting machinery.

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Crossref · 10.1073/pnas.1410552111

Cites

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  • SNX27 regulates cargo recycling by engaging with the Retromer complex, a SNX-BAR dimer, and the WASH complex.

    “SNX27 regulates cargo recycling by engaging with the Retromer complex (VPS35, VPS26A/B, and VPS29), a SNX–Bin/Amphiphysin/Rvs (BAR) dimer (SNX1/2 in complex with SNX5/6), and the WASH complex”

    From PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity (2025) · cites this paper as Gallon et al., 2014

    The Abstract and Results establish that SNX27 engages the VPS26A or VPS26B subunit of retromer to regulate cargo recycling. The Discussion identifies WASH as a retromer interactor, but does not establish direct engagement between SNX27 and WASH; our copy also does not establish engagement with the specified SNX-BAR dimer. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Both retromer and retriever are trimeric assemblies that share VPS29 and can utilize specific SNX proteins to identify cargo.

    “Both retromer and retriever are trimeric assemblies that share one common subunit (VPS29), and can utilize specific SNX proteins to identify cargo in the endosomal compartment14,15,20.”

    From Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling (2019) · cites this paper as [15]

    The Abstract identifies retromer as a VPS26–VPS29–VPS35 heterotrimer and describes SNX27 as an endosomal cargo adaptor for retromer. The paper does not address retriever, so it cannot establish that retriever is trimeric, shares VPS29, or uses SNX proteins to identify cargo. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Various sorting nexin proteins, such as SNX27, SNX32, SNX1-SNX6, and SNX1-SNX5, are autoinhibited in the basal state, with cargo binding enhancing their association with Retromer or membranes.

    “Interestingly, various sorting nexin proteins, such as SNX2729, SNX326,39, SNX1-SNX628, and SNX1-SNX540, operate similarly, being autoinhibited in the basal state, with cargo binding enhancing their association with Retromer or membranes.”

    From Structural basis for Retriever-SNX17 assembly and endosomal sorting (2024) · cites this paper as [29]

    The Results report that SNX27 binds the retromer subunit VPS26A and that VPS26A binding increases SNX27’s affinity for cargo motifs. The cited paper does not establish basal autoinhibition or show that cargo binding enhances SNX27’s association with retromer or membranes; its measured effect runs in the other direction. This citation is attached to SNX27, not the other sorting nexins listed. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Through this dual interaction SNX27 regulates the retrieval and recycling of hundreds of cargoes to the plasma membrane.

    “Through this dual interaction SNX27 regulates the retrieval and recycling of hundreds of cargoes to the plasma membrane [26,29,31,58,59].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [58]

    The Abstract describes SNX27 binding both cargo motifs and the retromer subunit VPS26, and the Results show that disrupting the SNX27–VPS26 interaction prevents GLUT1 recycling to the plasma membrane. The paper reports more than 80 SNX27-retromer-dependent transmembrane cargoes, not hundreds; it does not establish the claimed number. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Endosomal retrieval and recycling is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain.

    “and is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [11]

    The Significance passage (page not specified) says SNX27 and retromer help retrieve proteins from endosomes, and the Discussion describes their assembly on the endosome membrane. Neither passage identifies a specialised endosomal nanodomain called the “retrieval sub-domain” or says that it orchestrates recycling. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Citations

Cites

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Metadata

Authors
Gallon, M., Clairfeuille, T., Steinberg, F., Mas, C., Ghai, R., Sessions, R. B., Teasdale, R. D., Collins, B. M., & Cullen, P. J.
Affiliations
  • The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom;
  • Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and
  • School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2014-08-18
Volume
111
Issue
35
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1410552111
Cited by
182
References
3
Language
en

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