title: Crystal Structure of the interleukin-15.interleukin-15 receptor alpha complex: insights into trans and cis presentation.
abstract: Interleukin (IL)-15 is a pleiotropic cytokine that plays a pivotal role in both innate and adaptive immunity. IL-15 is unique among cytokines due to its participation in a trans signaling mechanism in which IL-15 receptor alpha (IL-15Ralpha) from one subset of cells presents IL-15 to neighboring IL-2Rbeta/gammac-expressing cells. Here we present the crystal structure of IL-15 in complex with the sushi domain of IL-15Ralpha. The structure reveals that the alpha receptor-binding epitope of IL-15 adopts a unique conformation, which, together with amino acid substitutions, permits specific interactions with IL-15Ralpha that account for the exceptionally high affinity of the IL-15.IL-15Ralpha complex. Interestingly, analysis of the topology of IL-15 and IL-15Ralpha at the IL-15.IL-15Ralpha interface suggests that IL-15 should be capable of participating in a cis signaling mechanism similar to that of the related cytokine IL-2. Indeed, we present biochemical data demonstrating that IL-15 is capable of efficiently signaling in cis through IL-15Ralpha and IL-2Rbeta/gammac expressed on the surface of a single cell. Based on our data we propose that cis presentation of IL-15 may be important in certain biological contexts and that flexibility of IL-15Ralpha permits IL-15 and its three receptor components to be assembled identically at the ligand-receptor interface whether IL-15 is presented in cis or trans. Finally, we have gained insights into IL-15.IL-15Ralpha.IL-2Rbeta.gammac quaternary complex assembly through the use of molecular modeling.
authors.affiliation: RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Kanagawa, Japan.
authors.forename: Shaun K
authors.initials: SK
authors.lastname: Olsen
authors.forename: Naruhisa
authors.initials: N
authors.lastname: Ota
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kishishita
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Kukimoto-Niino
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Murayama
authors.forename: Hidemi
authors.initials: H
authors.lastname: Uchiyama
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Toyama
authors.forename: Takaho
authors.initials: T
authors.lastname: Terada
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Osami
authors.initials: O
authors.lastname: Kanagawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000737:chemistry / Q000378:metabolism; D019409:Interleukin-15 / Q000737:chemistry* / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary; D053647:Receptors, Interleukin-15 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000939:Epitopes; C508025:Il15ra protein, mouse; C508022:Il2rb protein, mouse; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D046912:Multiprotein Complexes; D053647:Receptors, Interleukin-15