Lipoprotein lipase. Molecular model based on the pancreatic lipase x-ray structure: consequences for heparin binding and catalysis.
Lipoprotein lipase and pancreatic lipase have about 30% sequence identity, suggesting a similar tertiary fold. Three-dimensional models of lipoprotein lipase were constructed, based upon two recently determined x-ray crystal structures of pancreatic lipase, in which the active site was in an open and closed conformation, respectively. These models allow us to propose a few hypotheses on the structural determinants of lipoprotein lipase which are responsible for heparin binding, dimer formation, and phospholipase activity. The folding of the protein assembles a number of positive charge clusters at the back of the molecule, opposite the active site. These clusters probably form the heparin binding site, as confirmed by recent site-directed mutagenesis experiments. The active sites of lipoprotein lipase and pancreatic lipase look very similar, except for the lid (a surface loop covering the catalytic serine in the inactive state). A different open (active) conformation of the lid in both enzymes may be responsible for their differing substrate specificities. Predictions of the nature of the lipoprotein lipase dimer remain elusive, although our model enabled us to propose a few possibilities.
van Tilbeurgh
H
H
Laboratory of Cristallisation et Macromolecules Biologiques-Centre National de la Recherche Scientifique, Faculté de Médecine Nord, Marseille, France.
Roussel
A
A
Lalouel
J M
JM
Cambillau
C
C
D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D004563:Electrochemistry; D006801:Humans; D008049:Lipase / Q000648:ultrastructure; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000648:ultrastructure*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010179:Pancreas / Q000201:enzymology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D046911:Macromolecular Substances; D008049:Lipase; D008071:Lipoprotein Lipase