ArticleJournal of molecular biology2016
Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?
Article in Journal of molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 51 citations in OpenAlex.
- Consumption of Cuban Policosanol Improves Blood Pressure and Lipid Profile via Enhancement of HDL Functionality in Healthy Women Subjects: Randomized, Double-Blinded, and Placebo-Controlled Study.Oxidative medicine and cellular longevity · 2018Trial
- 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
- Role of complementarity-determining regions 1 and 3 in pathologic amyloid formation by human immunoglobulin κ1 light chains.Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2023Article
- 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
- Biochemical and hydrogen-deuterium exchange studies of the single nucleotide polymorphism Y649C in human platelet 12-lipoxygenase linked to a bleeding disorder.Archives of biochemistry and biophysics · 2023Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Autophagy Alteration in ApoA-I Related Systemic Amyloidosis.International journal of molecular sciences · 2022Article
- Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.Biophysical chemistry · 2022Review
- A Conservative Point Mutation in a Dynamic Antigen-binding Loop of Human Immunoglobulin λ6 Light Chain Promotes Pathologic Amyloid Formation.Journal of molecular biology · 2021Article
- Lipids and Lipoproteins in Health and Disease: Focus on Targeting Atherosclerosis.Biomedicines · 2021Review
- Novel parameter based on lipid indicators ratio improves prognostic value of plasma lipid levels in resectable colorectal cancer patients.World journal of gastrointestinal surgery · 2021Article
- [Correlation between Pretreatment Serum Apolipoprotein Level and Prognosis of Small Cell Lung Cancer Patients].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2020Article
- Novel clinical manifestations and treatment of hereditary apoA-I amyloidosis: when a good protein turns bad.Kidney international · 2020Article
- Amyloid Proteins and Peripheral Neuropathy.Cells · 2020Review
- Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis.The Journal of biological chemistry · 2020Article
- Structural Basis for Lipid Binding and Function by an Evolutionarily Conserved Protein, Serum Amyloid A.Journal of molecular biology · 2020Article
- Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles.Communications biology · 2020Article
- Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins.Frontiers in neuroscience · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
ApoA-I, the major protein of plasma high-density lipoprotein, removes cellular cholesterol and protects against atherosclerosis. ApoA-I mutations can cause familial amyloidosis, a life-threatening disease wherein N-terminal protein fragments form fibrils in vital organs. To unveil the protein misfolding mechanism and to understand why some mutations cause amyloidosis while others do not, we analyzed the structure, stability, and lipid-binding properties of naturally occurring mutants of full-length human apoA-I causing either amyloidosis (G26R, W50R, F71Y, and L170P) or aberrant lipid metabolism (L159R). Global and local protein conformation and dynamics in solution were assessed by circular dichroism, fluorescence, and hydrogen-deuterium exchange mass spectrometry. All mutants showed increased deuteration in residues 14-22, supporting our hypothesis that decreased protection of this major amyloid "hot spot" can trigger protein misfolding. In addition, L159R showed local helical unfolding near the mutation site, consistent with cleavage of this mutant in plasma to generate the labile 1-159 fragment. Together, the results suggest that reduced protection of the major amyloid "hot spot", combined with the structural integrity of the native helix bundle conformation, shifts the balance from protein clearance to β-aggregation. A delicate balance between the overall structural integrity of a globular protein and the local destabilization of its amyloidogenic segments may be a fundamental determinant of this and other amyloid diseases. Furthermore, mutation-induced conformational changes observed in the helix bundle, which comprises the N-terminal 75% of apoA-I, and its flexible C-terminal tail suggest the propagation of structural perturbations to distant sites via an unexpected template-induced ensemble-based mechanism, challenging the classical structure-based view.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.