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Journal of Lipid Research, Vol. 42, 894-901, June 2001
Copyright © 2001 by Lipid Research, Inc.

Research Articles

Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE

Correspondence to: Sissel Lund-Katz, To whom correspondence should be addressed.

To understand the molecular basis for the differences in receptor-binding activity of the three common human apolipoprotein E (apoE) isoforms, we characterized the microenvironments of their LDL receptor (LDLR)-binding regions (residues 136;–150). When present in dimyristoyl phosphatidylcholine (DMPC) complexes, the 22-kDa amino-terminal fragments (residues 1;–191) of apoE3 and apoE4 bound to the LDLR with 100-fold greater affinity than the 22-kDa fragment of apoE2. The pK_a values of lysines (K) at positions 143 and 146 in the LDLR-binding region in DMPC-associated 22-kDa apoE fragments were 9.4 and 9.9 in apoE2, 9.5 and 9.2 in apoE3, and 9.9 and 9.4 in apoE4, respectively. The increased pK_a of K146 in apoE2 relative to apoE3 arises from a reduction in the positive electrostatic potential in its microenvironment. This effect occurs because C158 in apoE2, unlike R158 in apoE3, rearranges the intrahelical salt bridges along the polar face of the amphipathic -helix spanning the LDLR-binding region, reducing the effect of the R150 positive charge on K146 and concomitantly decreasing LDLR-binding affinity.

The C112R mutation in apoE4 that differentiates it from apoE3 did not perturb the pK_a of K146 significantly, but it increased the pK_a of K143 in apoE4 by 0.4 pH unit. This change did not alter LDLR-binding affinity. Therefore, maintaining the appropriate positive charge at the C-terminal end of the receptor-binding region is particularly critical for effective interaction with acidic residues on the LDLR. — Lund-Katz, S., S. Wehrli, M. Zaiou, Y. Newhouse, K. H. Weisgraber, and M. C. Phillips. Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE. J. Lipid Res. 2001. 42: 894;–901.

Supplementary key words: apolipoprotein E2, apolipoprotein E3, apolipoprotein E4, lysine pK_a, amphipathic -helix, receptor-binding affinity

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