PhD ceremony Ms. A.A. Wasiel: Macrophage migration inhibitory factor. Cell surface receptor, enzymatic activities and evolutionary history of a multifunctional cytokine

PhD ceremony: Ms. A.A. Wasiel, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Macrophage migration inhibitory factor. Cell surface receptor, enzymatic activities and evolutionary history of a multifunctional cytokine

Promotor(s): prof. G.J. Poelarends, prof. W.J. Quax

Faculty: Mathematics and Natural Sciences

Macrophage migration inhibitory factor (MIF) is an important mammalian cytokine involved in innate and adaptive immune responses. Anna Wasiel has focused her attention on the intriguing evolutionary link of MIF to bacterial enzymes of the tautomerase superfamily.

Thirty years after its initial discovery in 1966, MIF was surprisingly found to also function as an enzyme catalyzing the tautomerization of phenylpyruvate, (p-hydroxyphenyl)pyruvate, and D-dopachrome. These catalytic activities and its three-dimensional structure link this mammalian cytokine to the tautomerase superfamily, which consists mainly of bacterial tautomerases.

Wasiel has investigated whether MIF-like proteins are present in bacteria and whether MIF shares promiscuous activities with other tautomerase superfamily enzymes. She found and characterized a MIF homologue from the free-living cyanobacterium Prochlorococcus marinus, which functions as a tautomerase sharing structural and mechanistic similarities with mammalian MIF. The discovery of a new subgroup of cyanobacterial proteins in the MIF family demonstrates that MIF-like proteins have a widespread distribution.

Inspired by the knowledge that protein relatives often share activities, Wasiel explored whether MIF exhibits additional catalytic activities. Intriguingly, she found that MIF possesses promiscuous dehalogenase activity towards trans-3-chloroacrylate. The finding that MIF shares tautomerase and dehalogenase activities with bacterial enzymes from the tautomerase superfamily provides additional evidence for divergent evolution from a common ancestral enzyme.

Finally, Wasiel developed a bacterial expression system to produce sufficient amounts of CD74, the human MIF receptor, which allows the investigation of its interaction with MIF and bacterial MIF-like molecules by SPR experiments and X-ray crystallography.