Ds. Dwyer, MOLECULAR-MODEL OF INTERLEUKIN-12 THAT HIGHLIGHTS AMINO-ACID-SEQUENCEHOMOLOGIES WITH ADHESION DOMAINS AND GASTROINTESTINAL PEPTIDES, Journal of molecular graphics, 14(3), 1996, pp. 148
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.