MIF PROTEINS ARE THETA-CLASS GLUTATHIONE-S-TRANSFERASE HOMOLOGS

MIF proteins are mammalian polypeptides of approximately 13,000 molecu lar weight. This class includes human macrophage migration inhibitory factor (MIF), a rat liver protein that has glutathione S-transferase ( GST) activity (TRANSMIF), and the mouse delayed early response gene 6 (DER6) protein. MIF proteins were previously linked to GSTs by demonst rating transferase activity and observing N-terminal sequence homology with a mu-class GST (Blocki, F.A., Schlievert, P.M., & Wackett, L.P., 1992, Nature 360, 269-270). In this study, MIF proteins are shown to be structurally related to the theta class of GSTs. This is establishe d in three ways. First, unique primary sequence patterns are developed for each of the GST gene classes. The patterns identify the three MIF proteins as theta-like transferase homologs. Second, pattern analysis indicates that GST members of the theta class contain a serine residu e in place of the N-terminal tyrosine that is implicated in glutathion e deprotonation and activation in GSTs of known structure (Liu, S., et al., 1992, J. Biol. Chem. 267, 42964299). The MIF proteins contain a threonine at this position. Third, polyclonal antibodies raised agains t recombinant human MIF cross-react on Western blots with rat theta GS T but not with alpha and mu GSTs. That MIF proteins have glutathione-b inding ability may provide a common structural key toward understandin g the varied functions of this widely distributed emerging gene family . Because theta is thought to be the most ancient evolutionary GST cla ss, MIF proteins may have diverged early in evolution but retained a g lutathione-binding domain.