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Review
. 2021 Apr 15:9:642378.
doi: 10.3389/fcell.2021.642378. eCollection 2021.

Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

Mintu Chandra  1   2 , Amy K Kendall  1   2 , Lauren P Jackson  1   2   3
Affiliations
Review

Toward Understanding the Molecular Role of SNX27/Retromer in Human Health and Disease

Mintu Chandra et al. Front Cell Dev Biol. .

Abstract

Aberrations in membrane trafficking pathways have profound effects in cellular dynamics of cellular sorting processes and can drive severe physiological outcomes. Sorting nexin 27 (SNX27) is a metazoan-specific sorting nexin protein from the PX-FERM domain family and is required for endosomal recycling of many important transmembrane receptors. Multiple studies have shown SNX27-mediated recycling requires association with retromer, one of the best-known regulators of endosomal trafficking. SNX27/retromer downregulation is strongly linked to Down's Syndrome (DS) via glutamate receptor dysfunction and to Alzheimer's Disease (AD) through increased intracellular production of amyloid peptides from amyloid precursor protein (APP) breakdown. SNX27 is further linked to addiction via its role in potassium channel trafficking, and its over-expression is linked to tumorigenesis, cancer progression, and metastasis. Thus, the correct sorting of multiple receptors by SNX27/retromer is vital for normal cellular function to prevent human diseases. The role of SNX27 in regulating cargo recycling from endosomes to the cell surface is firmly established, but how SNX27 assembles with retromer to generate tubulovesicular carriers remains elusive. Whether SNX27/retromer may be a putative therapeutic target to prevent neurodegenerative disease is now an emerging area of study. This review will provide an update on our molecular understanding of endosomal trafficking events mediated by the SNX27/retromer complex on endosomes.

Keywords: coat proteins; membrane traffic; retromer complex; sorting nexin 27; structural biology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of SNX27/retromer pathway in metazoan cells. Metazoan retromer is implicated in three distinct endosomal pathways through direct interactions with SNX proteins to form elongated tubules. The SNX27/retromer pathway is specific to metazoans and mediates cargo recycling from endosomes to the plasma membrane. In this pathway, cargoes including β2 adrenergic and glutamate receptors contain PDZ binding motifs recognized by SNX27. In addition, the SNX27 FERM domain binds NPxY motifs found in transmembrane cargoes. SNX-BAR/retromer and SNX3/retromer pathways occur in both yeast and metazoans. SNX-BAR/retromer retrieves cargoes from endosomes to the TGN, while SNX3/retromer is implicated in sorting receptors like Wntless (WLS) from endosomes to the TGN.
FIGURE 2
FIGURE 2
Sorting nexin 27 (SNX27) domain architecture. SNX27 contains a modular architecture with three established domains: the N-terminal PDZ domain (light blue), middle PX domain (gray), and C-terminal FERM domain (purple), which is divided into F1, F2, and F3 sub-domains. Key interactions in the SNX27/retromer pathway are indicated. VPS26 (dark blue) binds the PDZ domain. Ras binds the F1 sub-domain, and FAM21 engages both the SNX27 F3 sub-domain and retromer VPS35 subunit. All three SNX27 domains directly engage protein partners embedded in membranes enriched for PI3P.
FIGURE 3
FIGURE 3
Sorting nexin 27 (SNX27) interaction partners. Summary of reported binding partners for SNX27 structural domains.
FIGURE 4
FIGURE 4
Current structural overview of SNX27. (A–C) The SNX27 PDZ domain (purple ribbons) bound to PDZ binding motifs (green cylinders). These motifs can take three different forms: unphosphorylated (PDB ID: 4Z8J) shown in panel (A); phosphorylated at the –3 position (PDB ID: 5EMB) shown in panel (B); and phosphorylated at the –5 position (PDB ID: 5EM9) shown in panel (C). Phosphorylation state is a further way to module binding through increased affinity. (D) SNX27 PX domain shown in gray ribbons (PDB ID: 4HAS). (E) The SNX27 FERM domain model was generated from the X-ray crystal structure of SNX17 FERM domain bound to the NPxY motif found in P-selectin (PDB ID: 4GXB); the F1, F2, and F3 sub-domains are labeled.
FIGURE 5
FIGURE 5
Sorting nexin 27 (SNX27) binding to retromer and OTULIN. The SNX27 PDZ domain (light purple ribbons; PDB: 4Z8J) with a PDZbm (green cylinders) is shown with both VPS26 (dark blue ribbons; PDB ID: 4P2A) and OTULIN (yellow ribbons; PDB ID: 6SAK). Structural data suggest the interaction of SNX27 PDZ with retromer/cargo or OTULIN is mutually exclusive. OTULIN engages both the PDZbm site using a class I PDZbm and the β-hairpin required for interacting with VPS26.
FIGURE 6
FIGURE 6
Modeling SNX27/retromer on membranes. Thermophilic yeast SNX-BAR/retromer (PDB ID: 6H7W) (A) and mammalian SNX3/retromer coats (B) (PDB: not yet available) have been reconstituted in vitro. The view in panel (B) was generated using PDB: 5F0J, which approximates the reported SNX3/retromer architecture. Both complexes drive tubulation, and reconstructions indicate retromer forms conserved asymmetrical V-shaped arches across eukaryotes. VPS35 is shown as red ribbons, VPS26 as blue ribbons, VPS29 as green ribbons, Vps5 as yellow ribbons, and the SNX3 PX domain as gray ribbons. On each model, potential locations for SNX27 domains are marked. In the SNX-BAR/retromer model (A), the SNX27 PX domain (gray ribbons) appears to be occluded by BAR dimers, and the PDZ domain would likely be blocked from engaging membrane cargo by the BAR layer. In the SNX3/retromer model (B), the SNX27 PX (gray ribbons) and PDZ (purple ribbons) domains are both located close to the membrane. There are currently no structural data regarding the overall architecture of SNX27, either on its own or as part of a retromer coat, so the location of the FERM domain remains unknown. Both models assume the SNX27 PX occupies a similar location to SNX3 PX.
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