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Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis

Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling...

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Autores principales: Kim, Meewhi, Bezprozvanny, Ilya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126166/
https://www.ncbi.nlm.nih.gov/pubmed/34068576
http://dx.doi.org/10.3390/ijms22095030
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author Kim, Meewhi
Bezprozvanny, Ilya
author_facet Kim, Meewhi
Bezprozvanny, Ilya
author_sort Kim, Meewhi
collection PubMed
description Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.
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spelling pubmed-81261662021-05-17 Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis Kim, Meewhi Bezprozvanny, Ilya Int J Mol Sci Communication Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis. MDPI 2021-05-10 /pmc/articles/PMC8126166/ /pubmed/34068576 http://dx.doi.org/10.3390/ijms22095030 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Kim, Meewhi
Bezprozvanny, Ilya
Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
title Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
title_full Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
title_fullStr Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
title_full_unstemmed Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
title_short Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
title_sort differences in recycling of apolipoprotein e3 and e4—ldl receptor complexes—a mechanistic hypothesis
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126166/
https://www.ncbi.nlm.nih.gov/pubmed/34068576
http://dx.doi.org/10.3390/ijms22095030
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