Functions of Sorting Nexin 17 Domains and Recognition Motif for P-selectin Trafficking

Knauth, Peter; Schlüter, Thomas; Czubayko, Martin; Kirsch, Cornelia; Florian, Volker; Schreckenberger, Susan; Hahn, Heidi; Bohnensack, Ralf

doi:10.1016/j.jmb.2005.02.004

Cited by 50 publications

(53 citation statements)

References 48 publications

(67 reference statements)

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“…Bridging by water molecules facilitates several hydrogen bonds, and, critically, the upstream F −5 of the peptide is involved in a stacking interaction with SNX17 Trp321. Indeed in P-selectin the F −5 residue is important for SNX17 interaction (6), and the similar residues Y −5 in APP (10) and I −5 in LRP1 (15) also contribute to binding, suggesting that aromatic or bulky hydrophobic side chains at the −5 position impart an additional sequence specificity. Further contacts are made by peptide residue Y −8 with SNX17 Ser325, facilitated by a bridging water molecule.…”

Section: Resultsmentioning

confidence: 99%

“…Residues upstream of the core NAAY sequence also are docked into complementary surfaces of the SNX17 protein. In particular the docking of the F -5 residue into a hydrophobic groove capped by SNX17 Trp321 is striking, and previous mutagenesis experiments suggest that SNX17 may have a preference for binding either aromatic or bulky hydrophobic side chains at this site (6,10,15).…”

Section: Px-ferm Proteins Bind Promiscuously To a Large Variety Of Pumentioning

confidence: 91%

“…SNX17 is a member of the Phox-homology (PX) domain-containing protein family and has been shown to be a critical regulator of endosomal sorting and cell-surface recycling of several essential cargo molecules. These include P-selectin (6)(7)(8), amyloid precursor protein (APP) (9,10), integrins (11,12), and members of the LDL receptor family (13)(14)(15)(16)(17) via recognition of an NPxY or alternative NxxY signal. The PX proteins [often called "sorting nexins" (SNXs)] are a large family of molecules that govern diverse endosomal trafficking and signaling processes and, by definition, possess a phosphoinositide lipid-binding PX domain that promotes membrane recruitment (18)(19)(20).…”

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Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins

Ghai

Bugarčić

Liu

et al. 2013

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

125

151

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Transit of proteins through the endosomal organelle following endocytosis is critical for regulating the homeostasis of cell-surface proteins and controlling signal transduction pathways. However, the mechanisms that control these membrane-transport processes are poorly understood. The Phox-homology (PX) domain-containing proteins sorting nexin (SNX) 17, SNX27, and SNX31 have emerged recently as key regulators of endosomal recycling and bind conserved Asn-Pro-Xaa-Tyr-sorting signals in transmembrane cargos via an atypical band, 4.1/ezrin/radixin/moesin (FERM) domain. Here we present the crystal structure of the SNX17 FERM domain bound to the sorting motif of the P-selectin adhesion protein, revealing both the architecture of the atypical FERM domain and the molecular basis for recognition of these essential sorting sequences. We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins.endosome | protein crystallography | X-ray scattering | membrane trafficking T he cell-surface levels of signaling and adhesion receptors, nutrient transporters, ion channels, and many other proteins are tightly regulated by opposing endocytic, exocytic, and endosomal recycling transport pathways. The selective sorting of these transmembrane proteins is the consequence of their interaction with essential adaptor proteins via conserved motifs present in their cytosolic tails, generally based on short linear amino acid sequences such as the Yxxϕ, DxxLL, and [DE]xxxL [LI] motifs (where ϕ is any bulky hydrophobic side-chain, and x is any residue) recognized by clathrin adaptors (1-3). The first identified sorting signal was the Asn-Pro-Xaa-Tyr (NPxY) motif, initially described in the LDL receptor (LDLR) isolated from patients suffering from familial hypercholesterolemia, where mutation of the sequence results in defective internalization and cholesterol uptake (4). The recent structure of the autosomal recessive hypercholesterolemia protein (ARH) phosphotyrosinebinding (PTB) domain in complex with the LDLR intracellular domain (ICD) provides the molecular basis of LDLR recognition and internalization within clathrin-coated pits by endocytic adaptor proteins (5).Although little is known about the sorting sequences and mechanisms required for competing endosome-to-cell surface recycling pathways, emerging evidence shows that the NPxY motif not only is vital to internalization but also aids cargo recycling via organelle-specific recognition by the endosomal protein, sorting nexin 17 (SNX17). SNX17 is a member of the Phox-homology (PX) domain-containing protein family and has been shown to be a critical regulator of endosomal sorting and cell-surface recycling of several essential cargo molecules. These include P-selectin (6-8), amyloid precursor protein (APP) (9, 10), integrins (11,12), and members of the LDL receptor family (13-17) ...

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Section: Resultsmentioning

confidence: 99%

Section: Px-ferm Proteins Bind Promiscuously To a Large Variety Of Pumentioning

confidence: 91%

mentioning

confidence: 99%

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Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins

Ghai

Bugarčić

Liu

et al. 2013

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

125

151

View full text Add to dashboard Cite

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“…Previous studies have shown that the PX domain of these proteins binds with high specificity to PtdIns3P, driving their localization to PtdIns3P-enriched early endosomes Stockinger et al, 2002). PX-FERM proteins can then interact with cargo containing NPxY or NxxY motifs, and also PDZ-binding motif (PDZbm) cargo, in the case of SNX27, at the early endosomal membrane (Balana et al, 2011;Bottcher et al, 2012;Cai et al, 2011;Ghai et al, 2013;Hayashi et al, 2012;Joubert et al, 2004;Knauth et al, 2005;Lauffer et al, 2010;Lunn et al, 2007;Steinberg et al, 2013;Temkin et al, 2011;Valdes et al, 2011;Wang et al, 2013). This influences the routing of transmembrane cargo trafficking, away from degradative late endosomes and into recycling and retrieval pathways from the endosome back to the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide binding by the SNX27 FERM domain regulates localisation at the immune synapse of activated T-cells

Ghai

Tello-Lafoz

Norwood

et al. 2014

Journal of Cell Science

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Sorting nexin 27 (SNX27) controls the endosomal-to-cell-surface recycling of diverse transmembrane protein cargos. Crucial to this function is the recruitment of SNX27 to endosomes which is mediated by the binding of phosphatidylinositol-3-phosphate (PtdIns3P) by its phox homology (PX) domain. In T-cells, SNX27 localizes to the immunological synapse in an activation-dependent manner, but the molecular mechanisms underlying SNX27 translocation remain to be clarified. Here, we examined the phosphoinositide-lipid-binding capabilities of full-length SNX27, and discovered a new PtdInsPbinding site within the C-terminal 4.1, ezrin, radixin, moesin (FERM) domain. This binding site showed a clear preference for bi-and tri-phosphorylated phophoinositides, and the interaction was confirmed through biophysical, mutagenesis and modeling approaches. At the immunological synapse of activated T-cells, cell signaling regulates phosphoinositide dynamics, and we find that perturbing phosphoinositide binding by the SNX27 FERM domain alters the SNX27 distribution in both endosomal recycling compartments and PtdIns(3,4,5)P 3 -enriched domains of the plasma membrane during synapse formation. Our results suggest that SNX27 undergoes dynamic partitioning between different membrane domains during immunological synapse assembly, and underscore the contribution of unique lipid interactions for SNX27 orchestration of cargo trafficking.

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“…The PX domain of SNX17 plays important roles in the membrane localization of binding proteins through their binding to various phosphatidylinositol 3-phosphate (PtdIns(3)P). FERM domain and C-terminal region participate in cargo proteins like P-selectin, Patched and LRP binding (Florian et al, 2001;Williams et al, 2004;Knauth et al, 2005;van Kerkhof et al, 2005). The simplest model for SNX17 action is that it is an adaptor protein in KIF1Bβ dependent trafficking of LRP or P-selectin containing vesicle pools.…”

Section: Discussionmentioning

confidence: 99%

Sorting Nexin 17 Interacts Directly with Kinesin Superfamily KIF1Bβ Protein

Seog

Han

2008

Korean J Physiol Pharmacol

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KIF1Bβ is a member of the Kinesin superfamily proteins (KIFs), which are microtubule-dependent molecular motors that are involved in various intracellular organellar transport processes. KIF1Bβ is not restricted to neuronal systems, however, is widely expressed in other tissues, even though the function of KIF1Bβ is still unclear. To elucidate the KIF1Bβ-binding proteins in non-neuronal cells, we used the yeast two-hybrid system, and found a specific interaction of KIF1Bβ and the sorting nexin (SNX) 17. The C-terminal region of SNX17 is required for the binding with KIF1Bβ. SNX17 protein bound to the specific region of KIF1Bβ (813-916. aa), but not to other kinesin family members. In addition, this specific interaction was also observed in the Glutathione S-transferase pull-down assay. An antibody to SNX17 specifically co-immunoprecipitated KIF1Bβ associated with SNX17 from mouse brain extracts. These results suggest that SNX17 might be involved in the KIF1Bβ-mediated transport as a KIF1Bβ adaptor protein.

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Functions of Sorting Nexin 17 Domains and Recognition Motif for P-selectin Trafficking

Cited by 50 publications

References 48 publications

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins

Phosphoinositide binding by the SNX27 FERM domain regulates localisation at the immune synapse of activated T-cells

Sorting Nexin 17 Interacts Directly with Kinesin Superfamily KIF1Bβ Protein

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