Crystal Structure of the interleukin-15.interleukin-15 receptor alpha complex: insights into trans and cis presentation.
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.
Olsen
Shaun K
SK
RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Kanagawa, Japan.
Ota
Naruhisa
N
Kishishita
Seiichiro
S
Kukimoto-Niino
Mutsuko
M
Murayama
Kazutaka
K
Uchiyama
Hidemi
H
Toyama
Mitsutoshi
M
Terada
Takaho
T
Shirouzu
Mikako
M
Kanagawa
Osami
O
Yokoyama
Shigeyuki
S
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
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