ArticleThe FEBS journal2014
Amyloidogenic mutations in human apolipoprotein A-I are not necessarily destabilizing - a common mechanism of apolipoprotein A-I misfolding in familial amyloidosis and atherosclerosis.
Article in The FEBS journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 52 citations in OpenAlex.
- Structural Basis for the Pro-amyloidogenic Action and Ligand Binding of a Novel W72R Variant of Human Apolipoprotein A-I.Journal of molecular biology · 2026Article
- Cryo-EM reveals structural variability of apolipoprotein A-I amyloid fibrils across organs, mutations, and clinical presentations.Nature communications · 2026Article
- An unusual phenotype of hereditary AApoAI amyloidosis caused by a novel Asp20Tyr substitution is linked to pH-dependent aggregation of apolipoprotein A-I.Biochimica et biophysica acta. Molecular basis of disease · 2025Article
- Amyloidogenic 60-71 deletion/ValThr insertion mutation of apolipoprotein A-I generates a new aggregation-prone segment that promotes nucleation through entropic effects.Scientific reports · 2023Article
- The Apparent Organ-Specificity of Amyloidogenic ApoA-I Variants Is Linked to Tissue-Specific Extracellular Matrix Components.International journal of molecular sciences · 2022Article
- On the Aggregation of Apolipoprotein A-I.International journal of molecular sciences · 2022Article
- Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.Biophysical chemistry · 2022Review
- Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis.The Journal of biological chemistry · 2020Article
- A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function.Nature structural & molecular biology · 2020Article
- Mechanisms of aggregation and fibril formation of the amyloidogenic N-terminal fragment of apolipoprotein A-I.The Journal of biological chemistry · 2019Article
- High-efficient bacterial production of human ApoA-I amyloidogenic variants.Protein science : a publication of the Protein Society · 2018Article
- Molecular Insights into Human Hereditary Apolipoprotein A-I Amyloidosis Caused by the Glu34Lys Mutation.Biochemistry · 2018Article
- Lipid Bilayer Interactions of Amyloidogenic N-Terminal Fragment of Apolipoprotein A-I Probed by Förster Resonance Energy Transfer and Molecular Dynamics Simulations.Journal of fluorescence · 2018Article
- Effects of Disease-Causing Mutations on the Conformation of Human Apolipoprotein A-I in Model Lipoproteins.Biochemistry · 2018Article
- Article
- Immunochemical Approach for Monitoring of Structural Transition of ApoA-I upon HDL Formation Using Novel Monoclonal Antibodies.Scientific reports · 2017Article
- Structural stability and local dynamics in disease-causing mutants of human apolipoprotein a-I: what makes the protein amyloidogenic?Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2017Article
- Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?Journal of molecular biology · 2016Article
- Structural stability and functional remodeling of high-density lipoproteins.FEBS letters · 2015Review
- Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes.The Journal of biological chemistry · 2015Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
High-density lipoproteins and their major protein, apolipoprotein A-I (apoA-I), remove excess cellular cholesterol and protect against atherosclerosis. However, in acquired amyloidosis, nonvariant full-length apoA-I deposits as fibrils in atherosclerotic plaques; in familial amyloidosis, N-terminal fragments of variant apoA-I deposit in vital organs, damaging them. Recently, we used the crystal structure of Δ(185-243)apoA-I to show that amyloidogenic mutations destabilize apoA-I and increase solvent exposure of the extended strand 44-55 that initiates β-aggregation. In the present study, we test this hypothesis by exploring naturally occurring human amyloidogenic mutations, W50R and G26R, within or close to this strand. The mutations caused small changes in the protein's α-helical content, stability, proteolytic pattern and protein-lipid interactions. These changes alone were unlikely to account for amyloidosis, suggesting the importance of other factors. Sequence analysis predicted several amyloid-prone segments that can initiate apoA-I misfolding. Aggregation studies using N-terminal fragments verified this prediction experimentally. Three predicted N-terminal amyloid-prone segments, mapped on the crystal structure, formed an α-helical cluster. Structural analysis indicates that amyloidogenic mutations or Met86 oxidation perturb native packing in this cluster. Taken together, the results suggest that structural perturbations in the amyloid-prone segments trigger α-helix to β-sheet conversion in the N-terminal ~ 75 residues forming the amyloid core. Polypeptide outside this core can be proteolysed to form 9-11 kDa N-terminal fragments found in familial amyloidosis. Our results imply that apoA-I misfolding in familial and acquired amyloidosis follows a similar mechanism that does not require significant structural destabilization or proteolysis. This novel mechanism suggests potential therapeutic interventions for apoA-I amyloidosis.
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