Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis

Skeldal, Sune; Sykes, Alex M.; Glerup, Simon; Matusica, Dusan; Palstra, Nickless; Autio, Henri; Boskovic, Zoran; Madsen, Peder; Ċastrén, Eero; Nykjaer, Anders; Coulson, Elizabeth J.

doi:10.1074/jbc.m112.374710

Cited by 50 publications

(36 citation statements)

References 34 publications

(24 reference statements)

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“…Previous work demonstrated that phosphorylation of the cation-independent mannose 6-phosphate receptor on the cytoplasmic tail, which has high sequence similarity to sortilin, directly associates with its exit from the TGN (45). Previous studies indicate that, while the extracellular domain of sortilin associates with direct receptor interactions, the intracellular domain regulates its biological effects (46). The present study, which shows that sortilin-dependent calcification requires posttranslational modification of the C-terminus, supports this notion.…”

Section: Discussionsupporting

confidence: 78%

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Goettsch¹,

Hutcheson²,

Aikawa³

et al. 2016

Journal of Clinical Investigation

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206

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Section: Discussionsupporting

confidence: 78%

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Goettsch¹,

Hutcheson²,

Aikawa³

et al. 2016

Journal of Clinical Investigation

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209

206

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“…It seems reasonable to suggest that sorCS1b may also inhibit, or at least decrease, uptake of other soluble sortilin ligands that share the same binding site as α-Gal A and CNTF in the β-propeller domain of sortilin, e.g. As mentioned above sortilin associates with the p75 NTR , and engages both p75 NTR and pro-neurotrophins to form a death signalling trimeric complex [13,14,18,32]. Apart from soluble ligands, sortilin is also capable of interacting with other transmembrane proteins.…”

Section: Discussionmentioning

confidence: 98%

Human sorCS1 binds sortilin and hampers its cellular functions

Larsen

Hermey

Sørensen

et al. 2013

Biochemical Journal

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Sortilin and sorCS1 [sortilin-related Vps10p (vacuolar protein sorting/targeting protein 10) domain-containing receptor 1], both members of the Vps10p-D (Vps10p-domain) receptor family, are synthesized as precursor proteins and are converted into their mature form by enzymatic cleavage of a short N-terminal propeptide. SorCS1 does not bind its propeptide, but sortilin is able to bind not just its own propeptide, but also that of sorCS1. In the present study we show that the propeptide region of sorCS1 contains two separate sites for binding to sortilin and that only one of these sites is removed from human (as opposed to mouse) sorCS1 during processing. This leaves mature human sorCS1 with a sortilin-binding N-terminus, which allows formation of a complex between the two receptors in solution and on cell membranes. Furthermore, we find that the interaction with sorCS1 has a pronounced effect on sortilin's ability to mediate the cellular uptake of alternative ligands, and to hamper its facilitation of CNTF (ciliary neutrophic factor) signalling and the induction of phosphorylated STAT3 (signal transducer and activator of transcription 3). Thus the present study reveals a novel regulatory mechanism and suggest an entirely new role for sorCS1 as a modulator of sortilin function.

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“…Cells were serum starved for 3 h and subsequently treated with 3 nM NGF for 10 min before lysis. Proteins were cross-linked on ice before lysis with the membrane-permeable protein cross-linker dithiobis(succinimidylpropionate) (Pierce) and were immunoprecipitated as described previously (55).…”

Section: Methodsmentioning

confidence: 99%

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.

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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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Mapping of the Interaction Site between Sortilin and the p75 Neurotrophin Receptor Reveals a Regulatory Role for the Sortilin Intracellular Domain in p75 Neurotrophin Receptor Shedding and Apoptosis

Cited by 50 publications

References 34 publications

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Sortilin mediates vascular calcification via its recruitment into extracellular vesicles

Human sorCS1 binds sortilin and hampers its cellular functions

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

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