{"gene":"IL2RG","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2024,"finding":"A computationally designed binder targeting the intrinsically disordered region (IDR) of IL2RG (common gamma chain) was generated by RFdiffusion, achieving 10–100 nM affinity to a beta-strand conformation of the IDR, and was shown to colocalize with the receptor in cells, enabling modulation of IL2 signaling.","method":"RFdiffusion-based binder design targeting IDR in beta-strand conformation; binding affinity measured (10–100 nM Kd); cellular colocalization confirmed by imaging","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — single preprint, colocalization shown but no detailed mechanistic dissection of IL2RG function; primarily a binder-design study","pmids":["bio_10.1101_2024.07.16.603789"],"is_preprint":true},{"year":2025,"finding":"In an X-SCID mouse model (lacking functional IL2RG), ATM inhibition during HSC genome editing with Cas9/RNP and AAV donor DNA enhanced knock-in efficiency and restored expression of IL-2 receptor γ chain (CD132), confirming that IL2RG expression in HSCs can be rescued by HDR-based gene correction.","method":"Mouse X-SCID model; Cas9/RNP + AAV donor HDR editing; ATM inhibitor treatment; capillary western blotting for CD132 expression; transplantation assay for long-term engraftment","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — single preprint, functional restoration shown in a disease model but no direct mechanistic dissection of IL2RG protein function","pmids":["bio_10.1101_2025.09.03.673991"],"is_preprint":true}],"current_model":"IL2RG (common gamma chain) encodes a shared receptor subunit with an intrinsically disordered region capable of adopting beta-strand conformations that can be targeted by designed protein binders to modulate IL2 signaling, and its functional expression in hematopoietic stem cells can be restored by HDR-based genome editing; foundational mechanistic details of its signaling role (e.g., JAK3 recruitment, cytokine receptor complex assembly) are established in the broader literature but are not directly evidenced by the available abstracts in this corpus."},"narrative":{"teleology":[{"year":2024,"claim":"It was unknown whether the intrinsically disordered region of IL2RG could be specifically targeted by designed binders; RFdiffusion-generated binders demonstrated that this IDR adopts a beta-strand conformation amenable to high-affinity binding, establishing a new modality for modulating IL-2 signaling at the receptor level.","evidence":"Computational binder design (RFdiffusion) with biophysical affinity measurement (10–100 nM Kd) and cellular colocalization imaging (preprint)","pmids":["bio_10.1101_2024.07.16.603789"],"confidence":"Low","gaps":["Single preprint without peer review or independent replication","No mechanistic dissection of how binder engagement alters downstream JAK-STAT signaling","Structural basis of the IDR beta-strand conformation not resolved at atomic level"]},{"year":2025,"claim":"It was unclear whether HDR-based gene correction could efficiently restore IL2RG expression in HSCs for X-SCID therapy; ATM inhibition during Cas9/AAV editing enhanced knock-in and rescued CD132 expression and engraftment in an X-SCID mouse model, establishing feasibility of gene correction at the endogenous locus.","evidence":"X-SCID mouse model with Cas9/RNP + AAV donor HDR editing, ATM inhibitor treatment, capillary western blot for CD132, transplantation assay (preprint)","pmids":["bio_10.1101_2025.09.03.673991"],"confidence":"Low","gaps":["Single preprint without peer review or independent confirmation","No direct mechanistic analysis of IL2RG protein function or signaling reconstitution","Long-term immune reconstitution and safety in larger animal models not demonstrated"]},{"year":null,"claim":"The primary literature captured here does not provide direct experimental dissection of IL2RG's molecular signaling mechanism (e.g., JAK3 recruitment, cytokine receptor complex assembly, or downstream STAT activation); these foundational aspects remain unrepresented in the current discovery corpus.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural or biochemical characterization of IL2RG in cytokine receptor complexes from this corpus","No direct experimental data on JAK3 binding or STAT phosphorylation mediated by IL2RG","Mechanism by which IDR conformation influences receptor signaling is undefined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"IL2RG encodes the common gamma chain (γc), a shared cytokine receptor subunit essential for lymphocyte development and function, whose loss causes X-linked severe combined immunodeficiency (X-SCID). The extracellular domain contains an intrinsically disordered region capable of adopting a beta-strand conformation that can be targeted by computationally designed protein binders at 10–100 nM affinity to modulate IL-2 signaling [bio_10.1101_2024.07.16.603789]. Functional IL2RG expression in hematopoietic stem cells can be restored by HDR-based Cas9/AAV genome editing in an X-SCID mouse model, rescuing CD132 surface expression and supporting long-term engraftment [bio_10.1101_2025.09.03.673991]."},"prefetch_data":{"uniprot":{"accession":"P31785","full_name":"Cytokine receptor common subunit gamma","aliases":["Interleukin-2 receptor subunit gamma","IL-2 receptor subunit gamma","IL-2R subunit gamma","IL-2RG","gammaC","p64"],"length_aa":369,"mass_kda":42.3,"function":"Common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770)","subcellular_location":"Cell membrane; Cell surface","url":"https://www.uniprot.org/uniprotkb/P31785/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL2RG","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL2RG","total_profiled":1310},"omim":[{"mim_id":"616243","title":"TRANSMEMBRANE PROTEIN 131-LIKE; TMEM131L","url":"https://www.omim.org/entry/616243"},{"mim_id":"612086","title":"MINOR HISTOCOMPATIBILITY ANTIGEN, SERPIN DOMAIN-CONTAINING; HMSD","url":"https://www.omim.org/entry/612086"},{"mim_id":"608958","title":"ADENOSINE DEAMINASE; ADA","url":"https://www.omim.org/entry/608958"},{"mim_id":"607531","title":"KLF TRANSCRIPTION FACTOR 12; KLF12","url":"https://www.omim.org/entry/607531"},{"mim_id":"607003","title":"THYMIC STROMAL LYMPHOPOIETIN; TSLP","url":"https://www.omim.org/entry/607003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":109.3},{"tissue":"lymphoid tissue","ntpm":317.8}],"url":"https://www.proteinatlas.org/search/IL2RG"},"hgnc":{"alias_symbol":["CD132"],"prev_symbol":["SCIDX1","IMD4","CIDX"]},"alphafold":{"accession":"P31785","domains":[{"cath_id":"2.60.40.10","chopping":"54-153","consensus_level":"high","plddt":92.8873,"start":54,"end":153},{"cath_id":"2.60.40.10","chopping":"155-247","consensus_level":"high","plddt":94.2886,"start":155,"end":247},{"cath_id":"1.20.5","chopping":"255-289","consensus_level":"medium","plddt":82.7274,"start":255,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31785","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31785-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31785-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL2RG","jax_strain_url":"https://www.jax.org/strain/search?query=IL2RG"},"sequence":{"accession":"P31785","fasta_url":"https://rest.uniprot.org/uniprotkb/P31785.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31785/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31785"}},"corpus_meta":[{"pmid":null,"id":"bio_10.1101_2025.09.03.673991","title":"Transient ATM inhibition enhances knock-in efficiency in hematopoietic stem cells by attenuating the DNA damage response","date":"2025-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.03.673991","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.14.664835","title":"Humanized mice enable in vivo evaluation of engineered plasma cell biology and therapeutic function","date":"2025-07-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.14.664835","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.11.25322033","title":"The ClinGen Severe Combined Immunodeficiency Disease Variant Curation Expert Panel: Specifications for classification of variants in<i>ADA</i>,<i>DCLRE1C</i>,<i>IL2RG</i>,<i>IL7R</i>,<i>JAK3</i>,<i>RAG1</i>, and<i>RAG2</i>","date":"2025-02-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.11.25322033","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.27.645250","title":"The SRG RAT® supports human cell xenotransplantation through enhanced tumor microenvironment interactions","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.27.645250","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.16.603789","title":"Diffusing protein binders to intrinsically disordered proteins","date":"2024-07-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.16.603789","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4067,"output_tokens":661,"usd":0.011058},"stage2":{"model":"claude-opus-4-6","input_tokens":3834,"output_tokens":1036,"usd":0.067605},"total_usd":0.078663,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"A computationally designed binder targeting the intrinsically disordered region (IDR) of IL2RG (common gamma chain) was generated by RFdiffusion, achieving 10–100 nM affinity to a beta-strand conformation of the IDR, and was shown to colocalize with the receptor in cells, enabling modulation of IL2 signaling.\",\n      \"method\": \"RFdiffusion-based binder design targeting IDR in beta-strand conformation; binding affinity measured (10–100 nM Kd); cellular colocalization confirmed by imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single preprint, colocalization shown but no detailed mechanistic dissection of IL2RG function; primarily a binder-design study\",\n      \"pmids\": [\"bio_10.1101_2024.07.16.603789\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In an X-SCID mouse model (lacking functional IL2RG), ATM inhibition during HSC genome editing with Cas9/RNP and AAV donor DNA enhanced knock-in efficiency and restored expression of IL-2 receptor γ chain (CD132), confirming that IL2RG expression in HSCs can be rescued by HDR-based gene correction.\",\n      \"method\": \"Mouse X-SCID model; Cas9/RNP + AAV donor HDR editing; ATM inhibitor treatment; capillary western blotting for CD132 expression; transplantation assay for long-term engraftment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single preprint, functional restoration shown in a disease model but no direct mechanistic dissection of IL2RG protein function\",\n      \"pmids\": [\"bio_10.1101_2025.09.03.673991\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL2RG (common gamma chain) encodes a shared receptor subunit with an intrinsically disordered region capable of adopting beta-strand conformations that can be targeted by designed protein binders to modulate IL2 signaling, and its functional expression in hematopoietic stem cells can be restored by HDR-based genome editing; foundational mechanistic details of its signaling role (e.g., JAK3 recruitment, cytokine receptor complex assembly) are established in the broader literature but are not directly evidenced by the available abstracts in this corpus.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL2RG encodes the common gamma chain (γc), a shared cytokine receptor subunit essential for lymphocyte development and function, whose loss causes X-linked severe combined immunodeficiency (X-SCID). The extracellular domain contains an intrinsically disordered region capable of adopting a beta-strand conformation that can be targeted by computationally designed protein binders at 10–100 nM affinity to modulate IL-2 signaling [bio_10.1101_2024.07.16.603789]. Functional IL2RG expression in hematopoietic stem cells can be restored by HDR-based Cas9/AAV genome editing in an X-SCID mouse model, rescuing CD132 surface expression and supporting long-term engraftment [bio_10.1101_2025.09.03.673991].\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"It was unknown whether the intrinsically disordered region of IL2RG could be specifically targeted by designed binders; RFdiffusion-generated binders demonstrated that this IDR adopts a beta-strand conformation amenable to high-affinity binding, establishing a new modality for modulating IL-2 signaling at the receptor level.\",\n      \"evidence\": \"Computational binder design (RFdiffusion) with biophysical affinity measurement (10–100 nM Kd) and cellular colocalization imaging (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.16.603789\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single preprint without peer review or independent replication\",\n        \"No mechanistic dissection of how binder engagement alters downstream JAK-STAT signaling\",\n        \"Structural basis of the IDR beta-strand conformation not resolved at atomic level\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"It was unclear whether HDR-based gene correction could efficiently restore IL2RG expression in HSCs for X-SCID therapy; ATM inhibition during Cas9/AAV editing enhanced knock-in and rescued CD132 expression and engraftment in an X-SCID mouse model, establishing feasibility of gene correction at the endogenous locus.\",\n      \"evidence\": \"X-SCID mouse model with Cas9/RNP + AAV donor HDR editing, ATM inhibitor treatment, capillary western blot for CD132, transplantation assay (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.03.673991\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single preprint without peer review or independent confirmation\",\n        \"No direct mechanistic analysis of IL2RG protein function or signaling reconstitution\",\n        \"Long-term immune reconstitution and safety in larger animal models not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The primary literature captured here does not provide direct experimental dissection of IL2RG's molecular signaling mechanism (e.g., JAK3 recruitment, cytokine receptor complex assembly, or downstream STAT activation); these foundational aspects remain unrepresented in the current discovery corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural or biochemical characterization of IL2RG in cytokine receptor complexes from this corpus\",\n        \"No direct experimental data on JAK3 binding or STAT phosphorylation mediated by IL2RG\",\n        \"Mechanism by which IDR conformation influences receptor signaling is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}