Affinage

SNX2

Sorting nexin-2 · UniProt O60749

Round 2 corrected
Length
519 aa
Mass
58.5 kDa
Annotated
2026-04-28
40 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX2 is a PX- and BAR-domain-containing sorting nexin that functions as a membrane-targeting subunit of the mammalian retromer, forming interchangeable homodimers or heterodimers with SNX1 to bind PI(3)P-enriched, curved endosomal membranes and drive tubule formation required for cargo retrieval from endosomes to the trans-Golgi network (PMID:17101778, PMID:17891154). SNX2 and SNX1 are partially redundant: individual depletion impairs retrograde transport of cation-independent mannose 6-phosphate receptor and Shiga toxin, while combined loss causes near-complete trafficking failure (PMID:17101778, PMID:17498660). SNX2 also pairs with SNX6 in the ESCPE-1 complex, which deforms cargo-containing membranes but requires the adaptor VARP to recruit the VPS26–VPS29–VPS35 retromer trimer (PMID:17101778, PMID:19619496). Beyond retromer-dependent sorting, SNX2 interacts with the ER-resident protein VAPB to establish endosome–ER contact sites, cooperating with SNX1 to direct endosomal tubulation toward ER subdomains involved in autophagosome biogenesis during nutritional stress (PMID:36585258).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1998 Medium

    Identification of SNX2 as a PX-domain-containing protein that associates with receptor tyrosine kinases established it as a novel member of the sorting nexin family with potential roles in endosomal receptor trafficking.

    Evidence cDNA cloning and co-immunoprecipitation with EGFR, PDGFR, and insulin receptor in COS7 cells

    PMID:9819414

    Open questions at the time
    • Interaction with RTKs was based on overexpression Co-IP without reciprocal validation
    • Endogenous localization and function not yet addressed
  2. 2000 Medium

    Demonstration that SNX2 associates with the VPS26–VPS29–VPS35 complex placed it as the mammalian ortholog of yeast Vps5p and a bona fide retromer subunit.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and gel filtration chromatography in mammalian cells

    PMID:11102511

    Open questions at the time
    • Functional requirement for SNX2 in retromer-dependent cargo sorting not yet tested
    • Stoichiometry and domain requirements for retromer association undefined
  3. 2006 High

    Defining the retromer as two autonomously assembling subcomplexes — a VPS26–VPS29–VPS35 trimer and an SNX1/SNX2 dimer — and showing that loss of both SNX1 and SNX2 disrupts CI-MPR retrieval resolved the functional architecture of mammalian retromer and established SNX2's essential, partially redundant role in endosome-to-TGN cargo sorting.

    Evidence Biochemical fractionation, co-immunoprecipitation, and siRNA knockdown with CI-MPR trafficking assays in HeLa cells

    PMID:17101778

    Open questions at the time
    • Structural basis for SNX1/SNX2 interchangeability not determined
    • Cargo selectivity between SNX1- and SNX2-containing complexes unknown
  4. 2007 High

    Structural and functional studies revealed that the PX and BAR domains of SNX1/SNX2 bind PI(3)P-enriched curved membranes, explaining how the sorting nexin dimer targets retromer to endosomal tubules and mediates retrograde transport of toxins such as Shiga toxin.

    Evidence X-ray crystallography and EM of the VPS26–VPS29–VPS35 complex; siRNA knockdown with Shiga toxin trafficking in Vero cells

    PMID:17498660 PMID:17891154

    Open questions at the time
    • No crystal structure of the SNX2 BAR domain itself
    • Mechanism by which SNX-BAR tubulation is coordinated with cargo capture not resolved
  5. 2009 Medium

    Mapping of four distinct SNX-BAR dimer combinations (SNX1/SNX2 with SNX5/SNX6) revealed combinatorial retromer diversity, with SNX1 linking to the TGN tether Rab6IP1, suggesting distinct functional specialization within the SNX-BAR pool.

    Evidence Biochemical fractionation, co-immunoprecipitation, and C. elegans genetics

    PMID:19619496

    Open questions at the time
    • Specific cargo routed by each SNX-BAR combination not systematically assigned
    • Whether SNX2-containing dimers also contact TGN tethers is untested
  6. 2022 Medium

    Discovery that SNX2 interacts with the ER protein VAPB to regulate endosome–ER contact sites and direct endosomal tubulation toward autophagosome biogenesis sites during starvation uncovered a retromer-independent role in inter-organelle tethering and autophagy initiation.

    Evidence Live imaging, siRNA knockdown, co-immunoprecipitation, and starvation-induced autophagy assays

    PMID:36585258

    Open questions at the time
    • Structural basis of SNX2–VAPB interaction not determined
    • Whether this function extends beyond nutritional stress conditions is unknown
    • Single-laboratory finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for SNX2-specific functions versus SNX1, the cargo selectivity of individual SNX-BAR dimer combinations, and the in vivo physiological consequences of SNX2 loss in mammalian organisms.
  • No SNX2-specific crystal or cryo-EM structure available
  • No mouse knockout phenotype reported in the timeline
  • Mechanism coupling SNX2-mediated tubulation to VAPB-dependent autophagy signaling uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 5 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 2 R-HSA-9612973 Autophagy 2
Partners
SNX1SNX5SNX6VAPBVPS26VPS29VPS35
Complex memberships
ESCPE-1 (SNX2/SNX6)Retromer (SNX-BAR subcomplex)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SNX2 was identified as a novel sorting nexin with a conserved PX (phox homology) domain, found partially associated with cellular membranes, and shown to coimmunoprecipitate with receptor tyrosine kinases including EGF receptor, PDGF receptor, and insulin receptor when expressed in COS7 cells. cDNA cloning, coimmunoprecipitation in COS7 cells Molecular and cellular biology Medium 9819414
2000 SNX2, as a mammalian ortholog of yeast Vps5p, was found to associate with the putative retromer complex components hVps26, hVps29, and hVps35, which co-elute as a large complex (~220–440 kDa) by gel filtration chromatography. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, gel filtration chromatography Molecular biology of the cell Medium 11102511
2001 SNX2 was identified as a protein interaction partner of FBP17 (formin-binding protein 17) by yeast two-hybrid screening of a human kidney library, providing a link between the EGF receptor pathway and MLL fusion proteins. Yeast two-hybrid screen Proceedings of the National Academy of Sciences of the United States of America Low 11438682
2006 The mammalian retromer assembles as two autonomously assembling subcomplexes: a Vps26-Vps29-Vps35 obligate heterotrimer and an SNX1/2 alternative heterodimer or homodimer. Association of Vps26-Vps29-Vps35 with endosomes requires either SNX1 or SNX2, while SNX1/2 can be recruited to endosomes independently. Both SNX1 and SNX2 are interchangeable but essential for retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR) from endosomes to the TGN. Biochemical fractionation, co-immunoprecipitation, siRNA knockdown with CI-MPR trafficking assay in HeLa cells Molecular and cellular biology High 17101778
2007 SNX1 and SNX2 are required for retrograde transport of Shiga toxin from early endosomes to the trans-Golgi network; depletion of either SNX1 or SNX2 alone impaired Stx transport by ≥40%, while combined depletion caused ~80% inhibition, demonstrating partial redundancy. siRNA knockdown in Vero cells with Shiga toxin trafficking assay Biochemical and biophysical research communications Medium 17498660
2007 The retromer cargo-recognition VPS26-VPS29-VPS35 heterotrimer crystal structure was determined, and it was established that human retromer consists of this trimer plus a membrane-targeting heterodimer or homodimer of SNX1 and/or SNX2; SNX1/SNX2 subunits contain PX and BAR domains enabling binding to PI(3)P-enriched, curved endosomal membranes. X-ray crystallography of VPS29-VPS35 subcomplex, electron microscopy of intact VPS26-VPS29-VPS35 complex, interaction studies Nature High 17891154
2008 Review consolidating evidence that SNX1 and SNX2 are subunits of the mammalian retromer, forming a sorting nexin dimer (with SNX1, SNX2, SNX5, and/or SNX6) with PX and BAR domains that bind PI(3)P-enriched curved membranes of endosomal vesicles and tubules. Review synthesizing biochemical and structural data Current opinion in cell biology High 18472259
2009 Four mammalian retromer complexes were described with membrane-bound subcomplexes containing specific combinations of SNX1, SNX2, SNX5, and SNX6. SNX1 associates with the TGN-localized tether Rab6-interacting protein-1, establishing spatial organization of the retromer pathway. Biochemical fractionation, co-immunoprecipitation, C. elegans genetic studies Developmental cell Medium 19619496
2013 SNX2-ABL1 fusion protein, which lacks SH3 and SH2 domains present in BCR-ABL1, confers IL-3-independent proliferation when introduced into Ba/F3 cells, but shows reduced sensitivity to imatinib and dasatinib compared with BCR-ABL1-expressing cells. Retroviral transduction of Ba/F3 cells, IL-3-independent growth assay, TKI sensitivity assays Leukemia research Medium 24367893
2022 During nutritional starvation, SNX2 regulates endosome-ER contact sites through interaction with VAPB (an ER protein), and cooperates with SNX1 to induce endosomal membrane tubulation toward VAPB-positive ER subdomains involved in autophagosome biogenesis, establishing a non-retromer role for SNX2 in inter-organelle tethering during autophagy initiation. Live imaging, siRNA knockdown, co-immunoprecipitation, starvation-induced autophagy assay Life science alliance Medium 36585258
2023 SNX2, via its SNX-BAR domain, generates membrane tubulation from endosomal compartments and regulates endosome-ER contact sites through its interaction with VAP proteins at the ER membrane; SNX1 and SNX2 cooperation is required for tubulation of early endosomes toward ER sites during starvation-induced autophagy. Review consolidating imaging and biochemical data from the laboratory Contact (Thousand Oaks) Medium 38033809
2024 SNX2, as part of the ESCPE-1 complex (SNX2/SNX6), deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a reconstituted in vitro system using purified mammalian proteins; however, ESCPE-1 does not recruit Retromer to membranes on its own. VARP is required to reconstitute an endosomal supercomplex containing SNX27, ESCPE-1, and Retromer on PI(3)P-enriched membranes. Biochemical reconstitution with purified proteins, liposome tubulation assay, AlphaFold2 Multimer modeling, in vitro binding assays bioRxivpreprint Medium bio_10.1101_2024.07.11.603126

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2008 Retromer. Current opinion in cell biology 408 18472259
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2000 Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Molecular biology of the cell 254 11102511
2009 The retromer coat complex coordinates endosomal sorting and dynein-mediated transport, with carrier recognition by the trans-Golgi network. Developmental cell 250 19619496
2007 Functional architecture of the retromer cargo-recognition complex. Nature 249 17891154
1998 Identification of a family of sorting nexin molecules and characterization of their association with receptors. Molecular and cellular biology 216 9819414
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2006 Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors. Molecular and cellular biology 197 17101778
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2001 The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia. Proceedings of the National Academy of Sciences of the United States of America 70 11438682
2007 SNX1 and SNX2 mediate retrograde transport of Shiga toxin. Biochemical and biophysical research communications 50 17498660
2011 Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia. British journal of haematology 36 21391972
2022 Cancer-associated fibroblast-derived exosome miR-181b-3p promotes the occurrence and development of colorectal cancer by regulating SNX2 expression. Biochemical and biophysical research communications 30 36535076
2013 Poor responses to tyrosine kinase inhibitors in a child with precursor B-cell acute lymphoblastic leukemia with SNX2-ABL1 chimeric transcript. European journal of haematology 23 24215620
2013 Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1. Leukemia research 17 24367893
2022 A SNX1-SNX2-VAPB partnership regulates endosomal membrane rewiring in response to nutritional stress. Life science alliance 13 36585258
2023 Canonical and Non-Canonical Roles of SNX1 and SNX2 in Endosomal Membrane Dynamics. Contact (Thousand Oaks (Ventura County, Calif.)) 7 38033809
2014 Sorting Nexin 2 (SNX2): a potential marker of active thyrocytes in normal and hyperfunctioning thyroid disorders. Applied immunohistochemistry & molecular morphology : AIMM 3 23531855