Molecular Basis for the Differences in Lipid and Lipoprotein Binding Properties of Human Apolipoproteins E3 and E4

作者：Nguyen David; Dhanasekaran Padmaja; Nickel Margaret; Nakatani Ryosuke; Saito Hiroyuki; Phillips Michael C; Lund Katz Sissel^*

来源：Biochemistry, 2010, 49(51): 10881-10889.

DOI：10.1021/bi1017655

Human apolipoprotein (apo) E4 binds preferentially to very low-density lipoproteins (VLDLs), whereas apoE3 binds preferentially to high-density lipoproteins (HDLs), resulting in different plasma cholesterol levels for the two isoforms. To understand the molecular basis for this effect, we engineered the isolated apoE N-terminal domain (residues 1-191) and C-terminal domain (residues 192-299) together with a series of variants containing deletions in the C-terminal domain and assessed their lipid and lipoprotein binding properties. Both isoforms can bind to a phospholipid (PL)-stabilized triolein emulsion, and residues 261-299 are primarily responsible for this activity. ApoE4 exhibits better lipid binding ability than apoE3 as a consequence of a rearrangement involving the segment spanning residues 261-272 in the C-terminal domain. The strong lipid binding ability of apoE4 coupled with the VLDL particle surface being similar to 60% PL-covered is the basis for its preference for binding VLDL rather than HDL. ApoE4 binds much more strongly than apoE3 to VLDL but less strongly than apoE3 to HDL3, consistent with apoE lipid interactions being relatively unimportant for binding to HDL. The preference of apoE3 for binding to HDL3 arises because binding is mediated primarily by interaction of the N-terminal helix bundle domain with the resident apolipoproteins that cover similar to 80% of the HDL3 particle surface. Thus, the selectivity in the binding of apoE3 and apoE4 to HDL3 and VLDL is dependent upon two factors: (1) the stronger lipid binding ability of apoE4 relative to that of apoE3 and (2) the differences in the nature of the surfaces of VLDL and HDL3 particles, with the former being largely covered with PL and the latter with protein.

• 出版日期2010-12-28