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TitleA structural blueprint for interleukin-21 signal modulation.
Journal, issue, pagesCell Rep, Vol. 42, Issue 6, Page 112657, Year 2023
Publish dateJun 27, 2023
AuthorsGita C Abhiraman / Theodora U J Bruun / Nathanael A Caveney / Leon L Su / Robert A Saxton / Qian Yin / Shaogeng Tang / Mark M Davis / Kevin M Jude / K Christopher Garcia /
PubMed AbstractInterleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and ...Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and association with autoimmune disease. To better understand the structural basis of IL-21 signaling, we determine the structure of the IL-21-IL-21R-γc ternary signaling complex by X-ray crystallography and a structure of a dimer of trimeric complexes using cryo-electron microscopy. Guided by the structure, we design analogs of IL-21 by introducing substitutions to the IL-21-γc interface. These IL-21 analogs act as partial agonists that modulate downstream activation of pS6, pSTAT3, and pSTAT1. These analogs exhibit differential activity on T and B cell subsets and modulate antibody production in human tonsil organoids. These results clarify the structural basis of IL-21 signaling and offer a potential strategy for tunable manipulation of humoral immunity.
External linksCell Rep / PubMed:37339051 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.83 - 3.7 Å
Structure data

EMDB-28278: Hexameric IL-21 complex with IL-21R and IL-2Rg
Method: EM (single particle) / Resolution: 3.7 Å

PDB-8ent:
Interleukin-21 signaling complex with IL-21R and IL-2Rg
Method: X-RAY DIFFRACTION / Resolution: 2.83 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsCYTOKINE/CYTOKINE RECEPTOR / IL-21 / receptor / complex / signaling / CYTOKINE / CYTOKINE-CYTOKINE RECEPTOR complex

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