Overview

Our research focuses on the structural and functional relationships of apolipoprotein (apo) E in lipoprotein metabolism, heart disease, and neurodegenerative diseases, including Alzheimer’s disease (1). ApoE is a 299–amino acid, single-chain protein with two structural domains that also define functional domains (Figure 1).

The amino-terminal domain (residues 1–191) contains the low density lipoprotein (LDL) receptor–binding region (presumably the same region that interacts with other members of the LDL receptor family), and the carboxyl-terminal domain contains the major lipid-binding elements. The three common human isoforms, apoE2, apoE3, and apoE4, differ at two positions in the molecule and have very different metabolic properties and dramatic impacts on disease. ApoE3 (Cys-112,Arg-158) binds normally to the LDL receptor and is associated with normal lipid metabolism, whereas apoE2 (Cys-112,Cys-158) binds defectively to the LDL receptor and, under certain circumstances, is associated with the genetic disorder type III hyperlipoproteinemia. ApoE4 (Arg-112,Arg-158) binds normally to the LDL receptor but is associated with elevated cholesterol levels and an increased risk for cardiovascular disease. In addition, apoE4 is a major risk factor for Alzheimer’s disease.

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