DEFINITION AND SPATIAL LOCATION OF MOUSE INTERLEUKIN-2 RESIDUES THAT INTERACT WITH ITS HETEROTRIMERIC RECEPTOR

The high affinity receptor for interleukin-2 (IL-2) contains three sub units called IL-2R alpha, beta and gamma. A biological and receptor bi nding analysis based on 1393 different mutant mouse IL-2 (mIL-2) prote ins was used to define the function of each of the 149 residues. By th is genetic analysis, 44 residues were assigned important functions, 21 of which were structural. The remaining 23 residues consisted of 19 r esidues, from three separate regions, that were important for IL-2Ralp ha interaction; three residues, from two separate regions, that were i mportant for IL-2Rbeta interaction; and a single residue important for IL-2Rgamma interaction. We built a model mIL-2 structure based on the homologous human IL-2 (hIL-2) crystal structure. The roles of the 21 residues presumed to be important for structure were consistent with t he model. Despite discontinuity in the primary sequence, the residues specific for each IL-2R subunit interaction were clustered and located to three disparate regions of the tertiary mIL-2 structure. The relat ive spatial locations of these three surfaces are different from the t wo receptor binding sites known for the structurally related human gro wth hormone and the significance of this observation is discussed.