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PreprintCited by 4Cytokine Signaling Pathways and InteractionsPsoriasis: Treatment and PathogenesisReceptor Mechanisms and Signaling

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Structural basis for ACT1 oligomerization induced by IL-17 receptor hetero-tetramer

Open access
Zhang, Hui, Bai, Xiao-chen, Zhang, Xuewu·2025·Nature Communications
DOI 10.64898/2025.12.02.691943PMC PMC12828022

Preprint — published as 10.1038/s41467-025-67536-4 · Paper page

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Abstract

The IL-17 receptors (IL-17Rs) play critical roles in immunity and inflammatory diseases. IL-17-induced heteromeric complexes between IL-17RA and another IL-17R trigger signaling by binding the downstream transducer ACT1 through interactions between their intracellular SEF/IL-17R (SEFIR) domains. The molecular mechanism of this process remains unclear. Here we present the cryo-EM structure of the complex of IL-17RA, IL-17RB and ACT1, showing that the IL-17RA and IL-17RB SEFIR domains form an asymmetric hetero-tetramer. The two IL-17RA SEFIR domains serve as the base to recruit ACT1, while IL-17RB stabilizes the IL-17RA dimer but makes no interaction with ACT1. IL-17RB, IL-17RA and multiple ACT1 together form a double-stranded helical assembly. The C-terminal SEFIR extension (SEFEX) of IL-17RA acts as a molecular tendril to help anchor the ACT1 protomers. The structural model is supported by our mutational analyses. These findings reveal the basis for the formation for the signalosome of the IL-17 receptors and ACT1 critical for immune signaling.

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Metadata

Authors
Zhang, H., Bai, X.-C., & Zhang, X.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
  • Bai, Xiao-chen
  • Zhang, Xuewu
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2025-12-05
Volume
17
Issue
1
Pages
836-836
ISSN
2041-1723 (ISSN-L)
DOI
10.64898/2025.12.02.691943
PMC
PMC12828022
OpenAlex
W4417347193
Cited by
4
References
1
Citations by year
2026: 4
FWCI
1.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • PubMed Central (submittedVersion)
Funders
  • NIH (R35GM130289, R35GM156386)
  • Welch Foundation (I-1702, I-1944)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
IL-17 receptor, IL-17RA, IL-17RB, Act1, oligomerization, signalosome, IL-17 signaling, receptor complex structure, cryo-EM structure
MeSH terms
Protein Domains, Humans, Models, Molecular, Protein Binding, Signal Transduction, Cryoelectron Microscopy, Interleukin-17, Adaptor Proteins, Signal Transducing, Receptors, Interleukin-17, Protein Multimerization, HEK293 Cells

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