Crystal structure analysis of human autocrine motility factor

Introduction Autocrine motility factor (AMF) was originally identified by its ability to stimulate directional motility (chemotaxis) and random motility (chemokinetics) of the AMF-producing tumor cells. AMF stimulates cell motility and growth via a receptor-mediated signaling pathway involving morphological changes, receptor phosphorylation, a pertussis toxin-sensitive G-protein activation, inositol phosphate production, protein kinase C activation, and enhanced production of a metabolite of arachidonic acid. Recently, full-length cDNA cloning for both human and mouse AMF receptor (AMFR) genes has been reported and revealed that the AMFR is a novel type of seven transmembrane helix protein. Primary structure studies (cDNA cloning and amino acid sequencing) have identified human AMF (558 a.a.) as genetically identical to the extracellular cytokines (neuroleukin (NLK) and maturation factor (MF)), and highly homologous to the intracellular enzyme phosphohexose isomerase (PHI). The extracellular cytokines AMF/NLK/MF were originally identified to exist as a monomer in a solution, whereas the intracellular enzyme PHI was known to exist as a dimer in a solution. Recently, crystal structures of bacterial and rabbit PHIs have been reported and showed that both bacterial and rabbit PHI molecules exist as dimer in the crystal. Although the three-dimensional structures and quaternary structures of the intracellular enzyme PHI are now established, little is known of the tertiary structure, quaternary structure and structure-function relationship of the extracellular cytokines AMF/NLK/MF. Thus the three-dimensional structure of AMF is essential to clarify the structure-function relationship of the extracellular cytokines AMF/NLK/MF and to know how the intracellular enzyme PHI can be secreted and serve as a cytokine.