PDBsum entry 2psm

Cytokine

PDB id: 2psm

Contents

Protein chains

117 a.a. *

68 a.a. *

Ligands

BEN

Waters ×91

* Residue conservation analysis

PDB id:

2psm

Name:

Cytokine

Title:

Crystal structure of interleukin 15 in complex with interleukin 15 receptor alpha

Structure:

Interleukin-15. Chain: a, b. Synonym: il-15. Engineered: yes. Interleukin-15 receptor alpha chain. Chain: f, c. Fragment: unp residues 33-103. Synonym: il-15r-alpha, il- 15ra. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: il15. Expressed in: cell free synthesis. Other_details: cell free expression: e.Coli. Gene: il15ra. Other_details: cell free expression: e.Coli

Resolution:

2.19Å R-factor: 0.224 R-free: 0.236

Authors:

S.K.Olsen,K.Murayama,S.Kishishita,M.Kukimoto-Niino,T.Terada, M.Shirouzu,N.Ota,O.Kanagawa,S.Yokoyama,Riken Structural Genomics/proteomics Initiative (Rsgi)

Key ref:

S.K.Olsen et al. (2007). Crystal Structure of the Interleukin-15{middle dot}Interleukin-15 Receptor {alpha} Complex: INSIGHTS INTO TRANS AND CIS PRESENTATION. J Biol Chem, 282, 37191-37204. PubMed id: 17947230 DOI: 10.1074/jbc.M706150200

Date:

07-May-07 Release date: 06-Nov-07

Protein chains

P48346  (IL15_MOUSE) -  Interleukin-15 from Mus musculus

Seq: 162 a.a.

Struc: 117 a.a.*

Protein chains

Q60819  (I15RA_MOUSE) -  Interleukin-15 receptor subunit alpha from Mus musculus

Seq: 263 a.a.

Struc: 68 a.a.

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1074/jbc.M706150200

J Biol Chem 282:37191-37204 (2007)

PubMed id: 17947230

Crystal Structure of the Interleukin-15{middle dot}Interleukin-15 Receptor {alpha} Complex: INSIGHTS INTO TRANS AND CIS PRESENTATION.

S.K.Olsen, N.Ota, S.Kishishita, M.Kukimoto-Niino, K.Murayama, H.Uchiyama, M.Toyama, T.Terada, M.Shirouzu, O.Kanagawa, S.Yokoyama.

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 receptoralpha (IL-15Ralpha) from one subset of cells presents IL-15 to neighboring IL-2Rbeta/gamma(c)-expressing cells. Here we present the crystal structure of IL-15 in complex with the sushi domain of IL-15Ralpha. The structure reveals that thealpha 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/gamma(c) 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.gamma(c) quaternary complex assembly through the use of molecular modeling.

Selected figure(s)

Figure 3.
FIGURE 3. Comparison of surface electrostatic charge at the IL-15·IL-15R and IL-2·IL-2R interfaces. A, IL-15·IL-15R and B, IL-2·IL-2R complexes are shown as molecular surface representations in an open book view. Selected residues are labeled. Electrostatic potentials are mapped onto the molecular surfaces, with negative potential colored red and positive potential colored blue. Sites 1 and 2 of the IL-15·IL-15R complex and patches 1 and 2 of IL-2·IL-2R complex are indicated with a dashed cyan line and labeled. Note the presence of a negatively charged groove on IL-15 into which the three knobs of positive potential (Arg-25, Arg-27, and Arg-36) insert. The electrostatic potentials were calculated, and the figure was prepared using the program CCP4mg (38).

Figure 7.
FIGURE 7. Comparison of IL-15 quaternary complex model and IL-2 quaternary complex. The superimposed structures are shown as ribbon representations and are colored as in Fig. 6A. Note that the distinct conformation of the hA-hB loop of IL-15 places this region of the ligand into the vicinity of the hC-hC'1 loop of [c] where unique interactions can potentially take place. Also note the position and length of hA of IL-15 and IL-2 quaternary complex interface. IL-2 residues Leu-12, Glu-15, Leu-18, and Leu-19 from the N-terminal portion of hA participate in interactions at a three-way junction between IL-2·IL-2Rβ and [c] that is suggested to mediate cooperative binding. Due to the shorter hA of IL-15, it has no homologous residue to Leu-12 of IL-2. Furthermore, IL-2 residues Glu-15, Leu-18, and Leu-19 have diverged to Ile-3, Arg-6, and Tyr-7 in IL-15 making it unlikely that a homologous set of interactions takes place at the IL-15·IL-2Rβ/ [c] junction.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 37191-37204) copyright 2007.

Figures were selected by an automated process.