Human apoE3 and apoE4 differ from each another only at one amino acid residue at the position 112. ApoE3, the common isoform, has Cys-112, whereas apoE4 has Arg-1121,7,8. Structurally, apoE has two domains: the amino-terminal domain and the carboxyl-terminal domain, which contain the receptor-binding region and the lipid-binding region, respectively. The two domains are linked by a structurally flexible hinge region. Interaction between the carboxyl- and amino-terminal domains, called domain interaction, is a unique biophysical property of apoE41,7,8. In apoE4, domain interaction occurs as a result of a salt bridge formation between Arg-61 and Glu-255 due to the effect of Arg-112. This interaction occurs to a much less extent in apoE3 because the side chain of Arg-61 adopts a different conformation owing to Cys-112, resulting in a less accessible side chain conformation for a salt bridge formation with Glu-2551,7,8. Domain interaction has been suggested to be a molecular basis for apoE4’s detrimental effects in AD pathogenesis, and consequently has been pursued as a drug target to identify small molecule structure correctors capable of converting apoE4 to apoE3 both structurally and functionally1,7,8.
