Molecular Mechanisms of the R61T Mutation in Apolipoprotein E4: A Dynamic Rescue

The apolipoprotein E4 (ApoE4) gene is the strongest genetic risk factor for Alzheimer's disease (AD). With respect to the other common isoforms of this protein (ApoE2 and ApoE3), ApoE4 is characterized by lower stability that underlies the formation of a stable interaction between the protein's N- and C-terminal domains. AD-related cellular dysfunctions have been linked to this ApoE4 misfolded state. In this regard, it has been reported that the mutation R61T is able to rescue the deleterious cellular effects of ApoE4 by preventing the formation of the misfolded intermediate state. However, a clear description of the structural features at the basis of the R61T-ApoE4 mutant's protective effect is still missing. Recently, using extensive molecular dynamics simulations, we have identified a structural model of an ApoE4 misfolded intermediate state. Building on our previous work, here we explore the dynamical changes induced by the R61T mutation in the ApoE4 native and misfolded states. Notably, we do not observe any local changes in the domains in the R61T-ApoE4 system, rather a general loss of correlated movements in the entire protein structure. More specifically, we detect increased dynamics in the hinge region, which is essential for ApoE4 domain-domain interaction. Consistent with previously reported data on altered phospholipid and receptor binding, we hypothesize that mutations destabilizing the ApoE4 intermediate state change hinge region dynamics, which propagates to distal functional regions of the protein and modifies ApoE4's functional properties. This unique behavior of the ApoE4 hinge region provides, to our knowledge, a novel understanding of ApoE4's role in AD.