Open AccessStructure of the unique SEFIR domain from human interleukin 17 receptor A reveals a composite ligand‐binding site containing a conserved α‐helix for Act1 binding and IL‐17 signaling
Author(s) -
Zhang Bing,
Liu Caini,
Qian Wen,
Han Yue,
Li Xiaoxia,
Deng Junpeng
Publication year - 2014
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s1399004714005227
Subject(s) - helix (gastropod) , microbiology and biotechnology , receptor , helix bundle , protein structure , biology , binding site , ligand (biochemistry) , signal transduction , signal transducing adaptor protein , biophysics , basic helix loop helix , topology (electrical circuits) , chemistry , transcription factor , gene , dna binding protein , genetics , biochemistry , ecology , mathematics , combinatorics , snail
Interleukin 17 (IL‐17) cytokines play a crucial role in mediating inflammatory and autoimmune diseases. A unique intracellular signaling domain termed SEFIR is found within all IL‐17 receptors (IL‐17Rs) as well as the key adaptor protein Act1. SEFIR‐mediated protein–protein interaction is a crucial step in IL‐17 cytokine signaling. Here, the 2.3 Å resolution crystal structure of the SEFIR domain of IL‐17RA, the most commonly shared receptor for IL‐17 cytokine signaling, is reported. The structure includes the complete SEFIR domain and an additional α‐helical C‐terminal extension, which pack tightly together to form a compact unit. Structural comparison between the SEFIR domains of IL‐17RA and IL‐17RB reveals substantial differences in protein topology and folding. The uniquely long insertion between strand βC and helix αC in IL‐17RA SEFIR is mostly well ordered, displaying a helix (αCC′ ins ) and a flexible loop (CC′). The DD′ loop in the IL‐17RA SEFIR structure is much shorter; it rotates nearly 90° with respect to the counterpart in the IL‐17RB SEFIR structure and shifts about 12 Å to accommodate the αCC′ ins helix without forming any knots. Helix αC was identified as critical for its interaction with Act1 and IL‐17‐stimulated gene expression. The data suggest that the heterotypic SEFIR–SEFIR association via helix αC is a conserved and signature mechanism specific for IL‐17 signaling. The structure also suggests that the downstream motif of IL‐17RA SEFIR together with helix αC could provide a composite ligand‐binding surface for recruiting Act1 during IL‐17 signaling.