Comparative modeling of amoebapores and granulysin based on the NK-lysin structure-structural and functional implications.
Amoebapores, the pore-forming polypeptides of the protozoan parasite Entamoeba histolytica, and effector proteins of porcine and human lymphocytes, namely NK-lysin and granulysin, reveal a substantial sequence similarity despite 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 similarities, but also fundamental differences with respect to charge distribution, hydrophobicity and core packing. The combination of these structural properties and known biochemical data provides insight in the different membrane-interacting mechanisms of the proteins. For amoebapores, exposed hydrophobic grooves and a locally loosely packed protein core may allow a rearrangement of the protein and therefore may account for its ability to penetrate the target membrane and to form defined ion channels in planar lipid bilayers. In contrast, the structural features of NK-lysin and granulysin appear to be suitable for a membrane-perturbing mode of action rather than for channel formation.
Bruhn
H
H
Bernhard-Nocht-Institut für Tropenmedizin, Hamburg, Germany.
Leippe
M
M
D000595:Amino Acid Sequence; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry* / Q000378:metabolism; D007473:Ion Channels; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D011510:Proteolipids / Q000737:chemistry*; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D007473:Ion Channels; D008565:Membrane Proteins; C093238:NK-lysin; D011510:Proteolipids; D015800:Protozoan Proteins; D011663:Pulmonary Surfactants; C041670:amoebapore proteins, protozoan