Comparative modeling of amoebapores and granulysin based on the NK-lysin structure - Structure and functional implications

Amoebapores, the pore-forming polypeptides of the protozoan parasite Entamo eba histolytica, and effector proteins of porcine and human lymphocytes, na mely NK-lysin and granulysin, reveal a substantial sequence similiarity des pite their enormous evolutionary distance. Moreover, all these polypeptides display antibacterial activity and are in higher concentrations cytolytic to eukaryotic cells. The recently solved NMR structure of NK-lysin enabled us to build the three dimensional structures of amoebapores and granulysin by comparative modeling. The generated models revealed the expected similar ities, but also fundamental differences with respect to charge distribution , hydrophobicity and core packing. The combination of these structural prop erties and known biochemical data provides insight in the different membran e-interacting mechanisms of the proteins. For amoebapores, exposed hydropho bic grooves and a locally loosely packed protein core may allow a rearrange ment of the protein and therefore may account for its ability to penetrate the target membrane and to form defined ion channels in planar lipid bilaye rs. In contrast, the structural features of NK-lysin and granulysin appear to b e suitable for a membrane-perturbing mode of action rather than for channel formation.