Crystal Structure of the PX Domain of SNX27

Li, Y; Liao, Shanhui; Li, F; Zhu, Zhongliang

doi:10.1134/s0006297919020056

Cited by 3 publications

(3 citation statements)

References 22 publications

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“…The SNX27 Retromer cargo adaptor was also reported to associate with the WASH complex by coimmunoprecipitation (Steinberg et al, 2013). Responsible for recycling over 400 specific transmembrane cargoes from endosomes to the plasma membrane (Balana et al, 2011;Gallon et al, 2014;Ghai et al, 2011;Ghai et al, 2015;Steinberg et al, 2013), SNX27 is a peripheral membrane protein containing, from Ntermini to C-termini, PDZ, PX and FERM domains that mediate cargo selection, Retromer recruitment and protein-lipid interactions (Clairfeuille et al, 2016;Ghai et al, 2015;Li et al, 2019). Notably, SNX27 can bind via its FERM domain to acidic DLF (aDLF) motifs in the N-terminal disordered region of SNX1 and its homologue SNX2 within the BAR domain-containing ESCPE-1 complex (Simonetti et al, 2022;Yong et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex

Guo

Chen

Giménez-Andrés

et al. 2023

Preprint

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Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27-Retromer assembly interacts with the WASH complex which nucleates actin filaments establishing the endosomal reycling domain. Crystal structures, modelling, biochemical and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. However, mutation of the major VPS35-binding site does not inhibit cargo recycling, indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27-Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains.

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Section: Introductionmentioning

confidence: 99%

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex

Guo

Chen

Giménez-Andrés

et al. 2023

Preprint

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“…Structurally, the SNX27 PX domain (Figure 4D) adopts a globular fold containing three anti-parallel β-strands followed by three α-helices (Seet and Hong, 2006;Chandra and Collins, 2019;Li et al, 2019). Sequence alignments of SNX27 PX domain with other PX family members (Seet and Hong, 2006) indicate multiple conserved regions.…”

Section: Toward a Molecular Understanding Of Snx27/retromer Snx27 Structural Studiesmentioning

confidence: 99%

“…This includes specific basic residues, as well as the so-called "PPK loop" located between helices α1 and α2, which contains the consensus sequence defined as PxxPxK ( : large aliphatic amino acids V, I, L, and M) (Seet and Hong, 2006;Chandra and Collins, 2019;. The structure of SNX27 PX domain revealed a shallow and positively charged surface pocket in a location generally considered to be the binding site for negatively charged headgroups (Seet and Hong, 2006;Chandra and Collins, 2019;Li et al, 2019), although this structure did not explicitly contain the head group.…”

Section: Toward a Molecular Understanding Of Snx27/retromer Snx27 Structural Studiesmentioning

confidence: 99%

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

Chandra

Kendall

Jackson

2021

Front. Cell Dev. Biol.

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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.

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Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27–Retromer complex

Guo,

Chen,

Gimenez-Andres

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27–Retromer assembly interacts with the Wiskott–Aldrich syndrome protein and SCAR homolog (WASH) complex which nucleates actin filaments establishing the endosomal recycling domain. Crystal structures, modeling, biochemical, and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. Mutation of the major VPS35-binding site does not prevent cargo recycling; however, it partially reduces endosomal WASH association indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27–Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains.

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Crystal Structure of the PX Domain of SNX27

Cited by 3 publications

References 22 publications

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex

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

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27–Retromer complex

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