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Cited by 134Cellular transport and secretionReceptor Mechanisms and SignalingProtein Structure and Dynamics

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

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Ghai, Rajesh, Bugarcic, Andrea, Liu, Huadong, Norwood, Suzanne J., Skeldal, Sune, Coulson, Elizabeth J., Li, Shawn Shun-Cheng, Teasdale, Rohan D. +1 more·2013·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1216229110PMC PMC3581954
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Abstract

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.

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  • The region of SNX17 responsible for interaction with ApoER2 corresponds to amino acids 105-470, comprising the F1, F2, and F3 subdomains of the FERM domain and the C-terminal region.

    “We first determined that the region responsible for the interaction with ApoER2 corresponded to amino acids 105 to 470 of SNX17, which were translated to to the F1, F2 and F3 subdomains of the SNX17 FERM domain and the C-terminal region [35].”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [35]

    The section “Crystal Structure of the Atypical FERM Domain of SNX17” identifies F1, F2, and F3 as subdomains of the SNX17 FERM domain. However, the cited paper does not establish that SNX17 residues 105–470 interact with ApoER2 or that the C-terminal region participates in that interaction. Its “Molecular Biology and Protein Purification” section instead describes a 109–388 FERM construct fused to P-selectin. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The minimal sequence of SNX17 able to interact with the LDL-R receptor is residues 113-389, corresponding to the atypical FERM domain.

    “Using a yeast two-hybrid system, it was demonstrated that the minimal sequence of SNX17 able to interact with the LDL-R receptor is the region consisting of residues 113–389 [28], which strictly corresponds to the atypical FERM domain of SNX17 [35].”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [35]

    The “Crystal Structure of the Atypical FERM Domain of SNX17” section identifies and characterizes an atypical FERM domain in SNX17. Our copy does not give its boundaries as residues 113–389; searches for those residue numbers found no matching passage. The citing sentence attributes the yeast two-hybrid minimal-interaction result to a different reference, not to this paper. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Both the PX domain and the FERM domain are required for recruitment of SNX17 to the endosomal membrane.

    “Both the PX domain and the FERM domain, through binding to the cargo, are required for the recruitment of SNX17 to the endosomal membrane [35], [36].”

    From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [35]

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Research works printed but not linked: 46

  1. Kozik P, Francis RW, Seaman MN, Robinson MS (2010) A screen for endocytic motifs. Traffic 11(6):843-855.
  2. Pandey KN (2010) Small peptide recognition sequence for intracellular sorting. Curr Opin Biotechnol 21(5):611-620.
  3. Chen WJ, Goldstein JL, Brown MS (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 265(6):3116-3123.
  4. Dvir H, et al. (2012) Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail. Proc Natl Acad Sci USA 109(18):6916-6921.
  5. Knauth P, et al. (2005) Functions of sorting nexin 17 domains and recognition motif for P-selectin trafficking. J Mol Biol 347(4):813-825.
  6. Williams R, et al. (2004) Sorting nexin 17 accelerates internalization yet retards degradation of P-selectin. Mol Biol Cell 15(7):3095-3105.
  7. Florian V, Schlüter T, Bohnensack R (2001) A new member of the sorting nexin family interacts with the C-terminus of P-selectin. Biochem Biophys Res Commun 281(4): 1045-1050.
  8. Ghai R, et al. (2011) Phox homology band 4.1/ezrin/radixin/moesin-like proteins function as molecular scaffolds that interact with cargo receptors and Ras GTPases. Proc Natl Acad Sci USA 108(19):7763-7768.
  9. Lee J, et al. (2008) Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes. J Biol Chem 283(17): 11501-11508.
  10. Steinberg F, Heesom KJ, Bass MD, Cullen PJ (2012) SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J Cell Biol 197(2): 219-230.
  11. Böttcher RT, et al. (2012) Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail. Nat Cell Biol 14(6):584-592.
  12. Donoso M, et al. (2009) Polarized traffic of LRP1 involves AP1B and SNX17 operating on Y-dependent sorting motifs in different pathways. Mol Biol Cell 20(1):481-497.
  13. Betts GN, van der Geer P, Komives EA (2008) Structural and functional consequences of tyrosine phosphorylation in the LRP1 cytoplasmic domain. J Biol Chem 283(23): 15656-15664.
  14. van Kerkhof P, et al. (2005) Sorting nexin 17 facilitates LRP recycling in the early endosome. EMBO J 24(16):2851-2861.
  15. Burden JJ, Sun XM, García AB, Soutar AK (2004) Sorting motifs in the intracellular domain of the low density lipoprotein receptor interact with a novel domain of sorting nexin-17. J Biol Chem 279(16):16237-16245.
  16. Stockinger W, et al. (2002) The PX-domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor. EMBO J 21(16):4259-4267.
  17. Teasdale RD, Collins BM (2012) Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: Structures, functions and roles in disease. Biochem J 441(1):39-59.
  18. Cullen PJ (2008) Endosomal sorting and signalling: An emerging role for sorting nexins. Nat Rev Mol Cell Biol 9(7):574-582.
  19. Seet LF, Hong W (2006) The Phox (PX) domain proteins and membrane traffic. Biochim Biophys Acta 1761(8):878-896.
  20. Temkin P, et al. (2011) SNX27 mediates retromer tubule entry and endosome-to- plasma membrane trafficking of signalling receptors. Nat Cell Biol 13(6):715-721.
  21. Lauffer BE, et al. (2010) SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane. J Cell Biol 190(4):565-574.
  22. Lim KP, Hong W (2004) Human Nischarin/imidazoline receptor antisera-selected protein is targeted to the endosomes by a combined action of a PX domain and a coiled-coil region. J Biol Chem 279(52):54770-54782.
  23. Balana B, et al. (2011) Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27. Proc Natl Acad Sci USA 108(14):5831-5836.
  24. Schaff UY, et al. (2008) SLIC-1/sorting nexin 20: A novel sorting nexin that directs subcellular distribution of PSGL-1. Eur J Immunol 38(2):550-564.
  25. Elliott PR, et al. (2010) The Structure of the talin head reveals a novel extended conformation of the FERM domain. Structure 18(10):1289-1299.
  26. Hamada K, Shimizu T, Matsui T, Tsukita S, Hakoshima T (2000) Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain. EMBO J 19(17):4449-4462.
  27. Pearson MA, Reczek D, Bretscher A, Karplus PA (2000) Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101(3):259-270.
  28. Uhlik MT, et al. (2005) Structural and evolutionary division of phosphotyrosine binding (PTB) domains. J Mol Biol 345(1):1-20.
  29. Eck MJ, Dhe-Paganon S, Trüb T, Nolte RT, Shoelson SE (1996) Structure of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell 85(5): 695-705.
  30. Krissinel E, Henrick K (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372(3):774-797.
  31. Adachi H, Tsujimoto M (2010) Adaptor protein sorting nexin 17 interacts with the scavenger receptor FEEL-1/stabilin-1 and modulates its expression on the cell surface. Biochim Biophys Acta 1803(5):553-563.
  32. Bergant Maru si c M, Ozbun MA, Campos SK, Myers MP, Banks L (2012) Human papillomavirus L2 facilitates viral escape from late endosomes via sorting nexin 17. Traffic 13(3):455-467.
  33. Radzimanowski J, et al. (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. EMBO Rep 9(11):1134-1140.
  34. Anthis NJ, et al. (2009) The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J 28(22):3623-3632.
  35. Owen DJ, Setiadi H, Evans PR, McEver RP, Green SA (2001) A third specificity- determining site in mu 2 adaptin for sequences upstream of Yxx phi sorting motifs. Traffic 2(2):105-110.
  36. Alahari SK, Reddig PJ, Juliano RL (2004) The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK. EMBO J 23(14):2777-2788.
  37. Thomas EC, et al. (2006) The subcellular fractionation properties and function of insulin receptor substrate-1 (IRS-1) are independent of cytoskeletal integrity. Int J Biochem Cell Biol 38(10):1686-1699.
  38. Smith MJ, Hardy WR, Murphy JM, Jones N, Pawson T (2006) Screening for PTB domain binding partners and ligand specificity using proteome-derived NPXY peptide arrays. Mol Cell Biol 26(22):8461-8474.
  39. Kaburagi Y, et al. (1995) The role of the NPXY motif in the insulin receptor in tyrosine phosphorylation of insulin receptor substrate-1 and Shc. Endocrinology 136(8): 3437-3443.
  40. Li X, et al. (2012) Structural basis for small G protein effector interaction of Ras- related protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1). J Biol Chem 287(26):22317-22327.
  41. Ghai R, Collins BM (2011) PX-FERM proteins: A link between endosomal trafficking and signaling? Small GTPases 2(5):259-263.
  42. Cullen PJ (2011) Phosphoinositides and the regulation of tubular-based endosomal sorting. Biochem Soc Trans 39(4):839-850.
  43. Svergun DI, Petoukhov MV, Koch MH (2001) Determination of domain structure of proteins from X-ray solution scattering. Biophys J 80(6):2946-2953.
  44. Petoukhov MV, Svergun DI (2005) Global rigid body modeling of macromolecular complexes against small-angle scattering data. Biophys J 89(2):1237-1250.
  45. Bugarcic A, et al. (2011) Vps26A and Vps26B subunits define distinct retromer complexes. Traffic 12(12):1759-1773.
  46. Skeldal S, et al. (2012) 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. J. Biol. Chem. 287(52):43798- 43809.

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Authors
Ghai, R., Bugarcic, A., Liu, H., Norwood, S. J., Skeldal, S., Coulson, E. J., Li, S. S.-C., Teasdale, R. D., & Collins, B. M.
Affiliations
  • The University of Queensland (AU)
  • Institute for Molecular Bioscience and
  • Western University (CA)
  • Institute for Molecular Bioscience (AU)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2013-02-04
Volume
110
Issue
8
Pages
E643-52
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1216229110
PMC
PMC3581954
OpenAlex
W1995411796
Cited by
134
References
1
Citations by year
2026: 4 · 2025: 7 · 2024: 11 · 2023: 7 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 8 · 2018: 10 · 2017: 11 · 2016: 8 · 2015: 14 · 2014: 11 · 2013: 5
FWCI
7.35
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Australian Cancer Research Foundation
  • Australian Synchrotron
  • University of Queensland
  • Medical Research Council
  • Australian Research Council (DP0878608, DP120103930, FT100100027)
  • National Health and Medical Research Council (566727, FT100100027, 569601, 10012610)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
SNX17, SNX27, FERM domain, endosomal trafficking, endosomal recycling, P-selectin, receptor tyrosine kinase, crystal structure, membrane transport
MeSH terms
Amino Acid Sequence, Binding Sites, Models, Molecular, Molecular Sequence Data, Protein Conformation, Endosomes, Protein Transport, Sorting Nexins

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