NOVEL MECHANISM FOR DEFECTIVE RECEPTOR-BINDING OF APOLIPOPROTEIN E2 IN TYPE-III HYPERLIPOPROTEINEMIA

The defective binding of apolipoprotein (ape) E2 to lipoprotein recept ors, an underlying cause of type III hyperlipoproteinemia, results fro m replacement of Arg 158 with Cys, disrupting the naturally occurring salt bridge between Asp 154 and Arg 158. A new bond between Asp 154 an d Arg 150 is formed, shifting Arg 150 out of the receptor binding regi on. Elimination of the 154-150 salt bridge by site-directed mutagenesi s of Asp 154 to Ala restored the receptor binding activity to near nor mal levels. The X-ray crystal structure of apoE2 Ala 154 demonstrated that Arg 150 was relocated within the receptor binding region. Our res ults demonstrate that defective binding of apoE2 occurs by a novel mec hanism of the replacement of one salt bridge with another.