Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease

Abstract

Apolipoproteins E3 and E4, proteins with a molecular mass of 34.15 kDa, differ by a single amino acid change. ApoE4 contains an arginine residue at position 112, whereas apoE3 has a cysteine at this position. ApoE4 is the major risk factor for late-onset Alzheimer’s disease, whereas apoE3, the common isoform, is neutral with respect to this disease. Here, using literature data from both hydrogen-deuterium exchange and site-directed mutations, we suggest structural differences between these two isoforms that are distant from the site of the arginine-to-cysteine change. These structural differences involve sequences from both the N- and C-terminal domains, sequentially far apart but structurally close. In addition, these regions are close to regions that bind lipid and to a region involved in association of apoE monomers to higher molecular weight forms. We discuss the possibility that these regions could be targeted preferentially to affect the function of apoE4 relative to apoE3.

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

“…In the monomeric apoE3 variant, the C domain interacts with the N-terminal helix bundle domain through hydrogen bonds and salt bridges (16), especially involving the juxtaposition of residues 271-279 in the C domain with helix 4 (residues 131-164) in the N-domain bundle (22,23). Interaction of apoE with lipid surfaces is initiated by the C domain (24).…”

“…Importantly, the apoE4 C112R substitution is located in helix 3 (residues 89-125) of the N-terminal helix bundle, but the substitution also alters lipid-binding activity mediated by the C-terminal domain. This parallelism occurs because of altered domain−domain interactions in the apoE3 and E4 isoforms, variously explained by either altered salt-bridge formation (25) or allosteric effects (22,23,26). The bulky charged arginine residue in apoE4 acts directly to destabilize the N-terminal helix bundle and, indirectly, the C-terminal domain (15,27).…”

“…6) also contributes to the alteration in structure of the tetramer. The modified domain−domain interaction in apoE4 may be a consequence of the reoriented R61 side-chain modifying the charge distribution in the helix spanning residues 131 to 164, thereby perturbing the structure of the adjacent C-terminal helical residues 271-279 (22,23). Another contribution to the altered C-terminal domain organization in apoE4 may arise from perturbation of the hinge region by alteration of the hinge−helix bundle interaction through elimination of the R61−T194 hydrogen bond that exists in apoE3 (16) because of the R61 side-chain reorientation in apoE4.…”

Síndrome de Down, cerebro y desarrollo

“…Una mutación en este gen parece estar relacionada con la formación de las placas neuríticas características de la enfermedad de Alzheimer (Bertram & Tanzi, 2012). Una de las formas alélicas del gen de la apolipoproteína que probabiliza esta enfermedad es el alelo APO E4, el cual produce un tipo de apolipoproteína conocido como APO E. Poseer el alelo de la APO E supone un factor de riesgo crítico que predispone a la demencia en la adultez (Frieden & Garai, 2012). En el caso del síndrome de Down, existe un mayor riesgo de acumular β-amiloide derivada de la expresión de este alelo (Sabbagh, Fleisher, Chen, Rogers, Berk, Reiman et al, 2011), entre otras razones debido a que las células de estos individuos presentan genes en el par 21 por triplicado.…”

Assessment of Possible Association Between Antioxidant Levels and Apoe Gene Polymorphism in Demented Saudi Population

“…This amino substitution results in not only structural differences, but also physiologic differences such as their binding affinity for specific lipoprotein receptors, antioxidant properties, inflammatory responses and neuronal processes such as development and plasticity. Additionally, each of the APOE alleles is associated with differing risks of specific diseases (Mahley et al, 2006;Frieden & Garai, 2012;Liu et al, 2013).…”