Solution structure and dynamics of myeloid progenitor inhibitory factor-1 (MPIF-1), a novel monomeric CC chemokine

MPIF-1, a CC chemokine, is a specific inhibitor of myeloid progenitor cells and is the most potent activator of monocytes. The solution structure of m yeloid progenitor inhibitor factor-1 (MPIF-1) has been determined by NMR sp ectroscopy. The structure reveals that MPIF-1 is a monomer with a well defi ned core except for termini residues and adopts the chemokine fold of three beta -strands and an overlying alpha -helix. In addition to the four cyste ines that characterize most chemokines, MPIF-1 has two additional cysteines that form a disulfide bond. The backbone dynamics indicate that the disulf ide bonds and the adjacent residues that include the functionally important N-terminal and N-terminal loop residues show significant dynamics. MPIF-1 is a highly basic protein (pI >9), and the structure reveals distinct posit ively charged pockets that could be correlated to proteoglycan binding. MPI F-1 is processed from a longer proprotein at the N terminus and the latter is also functional though with reduced potency, and both proteins exist as monomers under a variety of solution conditions. MPIF-1 is therefore unique because longer pro-proteins of all other chemokines oligomerize in solutio n. The MPIF-1 structure should serve as a template for future functional st udies that could lead to therapeutics for preventing chemotherapy-associate d myelotoxicity.