title: Structural basis of interleukin-5 dimer recognition by its α receptor.
abstract: Interleukin-5 (IL-5), a major hematopoietin, stimulates eosinophil proliferation, migration, and activation, which have been implicated in the pathogenesis of allergic inflammatory diseases, such as asthma. The specific IL-5 receptor (IL-5R) consists of the IL-5 receptor α subunit (IL-5RA) and the common receptor β subunit (βc). IL-5 binding to IL-5R on target cells induces rapid tyrosine phosphorylation and activation of various cellular proteins, including JAK1/JAK2 and STAT1/STAT5. Here, we report the crystal structure of dimeric IL-5 in complex with the IL-5RA extracellular domains. The structure revealed that IL-5RA sandwiches the IL-5 homodimer by three tandem domains, arranged in a "wrench-like" architecture. This association mode was confirmed for human cells expressing IL-5 and the full-length IL-5RA by applying expanded genetic code technology: protein photo-cross-linking experiments revealed that the two proteins interact with each other in vivo in the same manner as that in the crystal structure. Furthermore, a comparison with the previously reported, partial GM-CSF•GM-CSFRA•βc structure enabled us to propose complete structural models for the IL-5 and GM-CSF receptor complexes, and to identify the residues conferring the cytokine-specificities of IL-5RA and GM-CSFRA.
authors.affiliation: RIKEN Systems and Structural Biology Center, Tsurumi-ku, Yokohama, Japan.
authors.forename: Seisuke
authors.initials: S
authors.lastname: Kusano
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Kukimoto-Niino
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Hino
authors.forename: Noboru
authors.initials: N
authors.lastname: Ohsawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikutani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
authors.forename: Kensaku
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Miki
authors.initials: M
authors.lastname: Hara-Yokoyama
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D015848:Interleukin-5 / Q000737:chemistry* / Q000378:metabolism*; D053666:Interleukin-5 Receptor alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
chemical_list: D015848:Interleukin-5; D053666:Interleukin-5 Receptor alpha Subunit