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TitleStructural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 2071, Year 2024
Publish dateMar 7, 2024
AuthorsScott Gardner / Yibo Jin / Paul K Fyfe / Tomas B Voisin / Junel Sotolongo Bellón / Elizabeth Pohler / Jacob Piehler / Ignacio Moraga / Doryen Bubeck /
PubMed AbstractIL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we ...IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.
External linksNat Commun / PubMed:38453915 / PubMed Central
MethodsEM (single particle)
Resolution3.06 - 3.16 Å
Structure data

18741

8qy4

EMDB-18741, PDB-8qy4:
Structure of interleukin 11 (gp130 P496L mutant).
Method: EM (single particle) / Resolution: 3.06 Å

18742

8qy5

EMDB-18742, PDB-8qy5:
Structure of interleukin 6.
Method: EM (single particle) / Resolution: 3.1 Å

18743

8qy6

EMDB-18743, PDB-8qy6:
Structure of interleukin 6 (gp130 P496L mutant).
Method: EM (single particle) / Resolution: 3.16 Å

Chemicals

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

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / interleukin / gp130

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