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 ident ity, suggesting a similar tertiary fold. Three-dimensional models of l ipoprotein lipase were constructed, based upon two recently determined x-ray crystal structures of pancreatic lipase, in which the active si te 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 f ormation, and phospholipase activity. The folding of the protein assem bles a number of positive charge clusters at the back of the molecule, opposite the active site. These clusters probably form the heparin bi nding site, as confirmed by recent site directed mutagenesis experimen ts. The active sites of lipoprotein lipase and pancreatic lipase look very similar, except for the lid (a surface loop covering the catalyti c serine in the inactive state). A different open (active) conformatio n of the lid in both enzymes may be responsible for their differing su bstrate specificities. Predictions of the nature of the lipoprotein li pase dimer remain elusive, although our model enabled us to propose a few possibilities.