Abstract
Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates cell migration in vitro and metastasis in vivo. AMF is genetically identical to the extracellular cytokines neuroleukin (NLK) and maturation factor (MF) and, interestingly, to the intracellular enzyme phosphoglucose isomerase (PGI) . The crystal structures of the inhibitor-free open form and the inhibitor-bound closed form of human AMF have been determined at 1.9 Å and 2.4 Å resolution, respectively. Upon inhibitor binding, local conformation changes occur around the inhibitor-binding site. The inhibitor-bound structure shows that the location of the inhibitor (of cytokine activity) binding site of human AMF is very similar to those of the inhibitor (of enzymatic activity) binding sites of PGIs. The present study clearly shows that there is structural overlap of the regions responsible for the enzymatic and cytokine functions of AMF/PGI and suggests two scenarios for the inhibition mechanism of cytokine activity of AMF by the carbohydrate phosphate.
