Molecular Mechanisms of the R61T Mutation in Apolipoprotein E4: A Dynamic Rescue
Open accessAbstract
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.
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In ApoE4, the Arg112 substitution is predicted to promote an intramolecular domain interaction between Arg61 and Glu255 that repositions the C-terminal domain, reducing lipid-binding efficiency and impairing intracellular trafficking.
“Although the tendency to self-association has precluded most attempts at a full length structure of ApoE it is predicted that in ApoE4, the Arg112 substitution promotes an intramolecular 'domain interaction' between Arg61 and Glu255 that repositions the C-terminal domain, reducing lipid-binding efficiency and impairing intracellular trafficking (11).”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [11]
The Introduction (p. 2192) describes an ApoE4 interdomain interaction that may involve Arg61 and Glu255, but also notes alternative hypotheses that do not involve that salt bridge. It reports improved intracellular trafficking after R61T mutation, and the discussion links hinge and C-terminal dynamics to altered lipid binding. Our copy does not identify Arg112 as the cause or establish that the proposed Arg61–Glu255 interaction repositions the C-terminal domain and thereby reduces lipid-binding efficiency and impairs trafficking. (LLM, conf=0.85)
Experimental — accuracy not yet measuredR61T is predicted to disrupt the Arg61-Glu255 salt bridge responsible for ApoE4 domain interaction without altering the C-terminal sequence.
“It is predicted that R61T disrupts the Arg61-Glu255 salt bridge responsible for ApoE4 domain interaction without altering the C-terminal sequence (11), and its normalisation of self-association to ApoE3 levels indicates that N-terminal domain interaction propagates allosterically to enhance C-terminal selfassociation in ApoE4.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [11]
The Results and Discussion (pp. 2194–2196) describe R61T as disrupting ApoE4 interdomain interaction, and the mutation is at position 61 rather than in the C-terminal sequence. The paper does not specifically say that R61T disrupts an Arg61–Glu255 salt bridge; those residues’ interaction appears in the title of a cited reference, not in the paper’s account of its own findings. (LLM, conf=0.83)
Experimental — accuracy not yet measuredN-terminal domain interaction propagates allosterically to enhance C-terminal self-association in ApoE4.
“It is predicted that R61T disrupts the Arg61-Glu255 salt bridge responsible for ApoE4 domain interaction without altering the C-terminal sequence (11), and its normalisation of self-association to ApoE3 levels indicates that N-terminal domain interaction propagates allosterically to enhance C-terminal selfassociation in ApoE4.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [11]
The discussion describes long-range communication and allosteric effects of mutations at residue 61 on ApoE4’s N- and C-terminal domains. The Results (p. 2196) also link R61T to weakened interdomain correlations. But the paper does not report that ApoE4’s N-terminal domain interaction enhances C-terminal self-association or that R61T normalizes self-association to ApoE3 levels. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe R61T mutant, which is predicted to disrupt domain interaction without altering the C-terminal sequence, normalizes signal in this assay to ApoE3 levels, providing mechanistic evidence that the N-terminal domain interaction of ApoE4 impacts self-association.
“The observation that the mutant R61T, which is predicted to disrupt domain interaction without altering the C-terminal sequence, normalizes signal in this assay to ApoE3 levels provides mechanistic evidence that while the C-terminal domain of ApoE is undoubtedly crucial for ApoE oligomerization, the N-terminal domain interaction of ApoE4 impacts self-association (11,12,24,25).”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [11]
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Experimental — accuracy not yet measuredThe enhanced self-association of ApoE4 relative to ApoE3 is mechanistically linked to N-terminal domain interaction, as the R61T variant restores signal to ApoE3-equivalent levels.
“We show that ApoE4 shows significantly greater self-association than ApoE3, and this enhanced selfassociation is mechanistically linked to N-terminal domain interaction as the R61T variant which is predicted to disrupt the Arg61-Glu255 salt bridge (11), restores signal to ApoE3-equivalent levels.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [11]
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Cites
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Apolipoprotein E4 Forms a Molten Globule
Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204898200 · Cited by 204 · see citing works
A Monomeric, Biologically Active, Full-Length Human Apolipoprotein E
Zhang, Y., Vasudevan, S., Sojitrawala, R., Zhao, W., Cui, C., Xu, C., Fan, D., Newhouse, Y., Balestra, R., Jerome, W. G., et al. (2007) · Biochemistry · doi:10.1021/bi700672v · Cited by 79 · see citing works
Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease
Tamboli, I. Y., Heo, D., & Rebeck, G. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093120 · Cited by 35 · see citing works
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Andrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
- Authors
- Williams, B., Convertino, M., Das, J., & Dokholyan, N. V.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Dokholyan, Nikolay V.
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 113
- Issue
- 10
- Pages
- 2192-2198
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC5700245
- OpenAlex
- W2755678219
- Cited by
- 5
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2019: 1
- FWCI
- 0.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NIH) (R01GM080742, R01GM11401, R01GM064803, R01GM123247)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- APOE ε4, Alzheimer's disease, protein misfolding, domain-domain interactions, protein stability, molecular dynamics simulation, protein conformational dynamics
- MeSH terms
- Amino Acid Sequence, Mutation, Protein Structure, Secondary, Apolipoprotein E4, Molecular Dynamics Simulation
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