Affinage

IL2RG

Cytokine receptor common subunit gamma · UniProt P31785

Length
369 aa
Mass
42.3 kDa
Annotated
2026-04-28
2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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].

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2024 Low

    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)

    PMID:bio_10.1101_2024.07.16.603789

    Open questions at the time
    • 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
  2. 2025 Low

    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)

    PMID:bio_10.1101_2025.09.03.673991

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 2

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 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. RFdiffusion-based binder design targeting IDR in beta-strand conformation; binding affinity measured (10–100 nM Kd); cellular colocalization confirmed by imaging bioRxivpreprint Low bio_10.1101_2024.07.16.603789
2025 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. 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 bioRxivpreprint Low bio_10.1101_2025.09.03.673991