ArticleJournal of molecular biology2011
A two-site mechanism for the inhibition of IAPP amyloidogenesis by zinc.
Article in Journal of molecular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 119 citations in OpenAlex.
- Impact of Stabilizing Osmolytes on the Conformational Dynamics of Human and Rat Islet Amyloid Polypeptides.Proteins · 2026Article
- Development of Petrelintide: a Potent, Stable, Long-Acting Human Amylin Analogue.Journal of medicinal chemistry · 2025Article
- Zinc and pH modulate the ability of insulin to inhibit aggregation of islet amyloid polypeptide.Communications biology · 2024Article
- Exploring the central region of amylin and its analogs aggregation: the influence of metal ions and residue substitutions.Frontiers in chemistry · 2024Article
- The Effect of Calcium Ions on hIAPP Channel Activity: Possible Implications in T2DM.Membranes · 2023Article
- Impact of CaBiochimica et biophysica acta. Biomembranes · 2023Article
- The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer's diseases.Diabetology & metabolic syndrome · 2023Review
- Zinc and iron dynamics in human islet amyloid polypeptide-induced diabetes mouse model.Scientific reports · 2023Article
- Zn(II) binding to pramlintide results in a structural kink, fibril formation and antifungal activity.Scientific reports · 2022Article
- Human islet amyloid polypeptide: A therapeutic target for the management of type 2 diabetes mellitus.Journal of pharmaceutical analysis · 2022Review
- Thermodynamic surprises of Cu(II)-amylin analogue complexes in membrane mimicking solutions.Scientific reports · 2022Article
- Regulation of divalent metal ions to the aggregation and membrane damage of human islet amyloid polypeptide oligomers.RSC advances · 2021Article
- α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine.Chemical science · 2021Article
- Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.Chemical reviews · 2021Review
- Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes.Chemical reviews · 2021Review
- Nucleobindin-2 consists of two structural components: The ZnComputational and structural biotechnology journal · 2021Article
- "What Doesn't Kill You Makes You Stronger": Future Applications of Amyloid Aggregates in Biomedicine.Molecules (Basel, Switzerland) · 2020Review
- Zinc boosts EGCG's hIAPP amyloid Inhibition both in solution and membrane.Biochimica et biophysica acta. Proteins and proteomics · 2019Article
- Influence of methionine-ruthenium complex on the fibril formation of human islet amyloid polypeptide.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2019Article
- Metal-dependent hormone function: the emerging interdisciplinary field of metalloendocrinology.Metallomics : integrated biometal science · 2019Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Human islet amyloid polypeptide (hIAPP) is a highly amyloidogenic protein co-secreted with insulin in response to glucose levels. The formation of hIAPP amyloid plaques near islet cells has been linked to the death of insulin-secreting β-cells in humans and the progression of type II diabetes. Since both healthy individuals and those with type II diabetes produce and secrete hIAPP, it is reasonable to look for factors involved in storing hIAPP and preventing amyloidosis. We have previously shown that zinc inhibits the formation of insoluble amyloid plaques of hIAPP; however, there remains significant ambiguity in the underlying mechanisms. In this study, we show that zinc binds unaggregated hIAPP at micromolar concentrations similar to those found in the extracellular environment. By contrast, the fibrillar amyloid form of hIAPP has low affinity for zinc. The binding stoichiometry obtained from isothermal titration calorimetry experiments indicates that zinc favors the formation of hIAPP hexamers. High-resolution NMR structures of hIAPP bound to zinc reveal changes in the electron environment along residues that would be located along one face of the amphipathic hIAPP α-helix proposed as an intermediate for amyloid formation. Results from electrospray ionization mass spectroscopy investigations showed that a single zinc atom is predominantly bound to hIAPP and revealed that zinc inhibits the formation of the dimer. At higher concentrations of zinc, a second zinc atom binds to hIAPP, suggesting the presence of a low-affinity secondary binding site. Combined, these results suggest that zinc promotes the formation of oligomers while creating an energetic barrier for the formation of amyloid fibers.
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