MOLECULAR-MODEL OF INTERLEUKIN-12 THAT HIGHLIGHTS AMINO-ACID-SEQUENCEHOMOLOGIES WITH ADHESION DOMAINS AND GASTROINTESTINAL PEPTIDES

A three-dimensional (3-D) model of both subunits of interleukin 12 (IL -12) has been created through molecular modeling. Initial assignment o f coordinates in the model of the p40 subunit was based on established amino acid sequence homology between the second and third domains of p40 and the human growth hormone receptor (GHR) and new observations o f similarity between the first domain of p40 and the N-terminal domain of CD4. Human growth hormone (GH) served as the reference protein for the p35 chain. Furthermore, thorough analysis of the amino acid seque nce of IL-12 revealed two distinct regions of the p40 subunit that dis play homology with other proteins. The first region (in domain two) co ntains the sequence RGD, which is found in adhesion proteins (such as fibronectin), and the nearby sequence VTCG, which occurs in a diverse set of molecules, including thrombospondin, properdin, and circumsporo zoite proteins of Plasmodium. The second region of homology spans the third domain of p40 and shows marked similarity with the gastrointesti nal peptides, such as secretin and glucagon and their preprohormones. We conclude (1) that the regions of homology define functionally impor tant segments of p40 that are fully exposed at the protein surface, an d (2) that the third domain of p40 (and its equivalent in the cytokine receptor family) is derived from the same ancestral genes as the gast rointestinal peptides.