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Journal of Molecular Biology Jan 2022Human amylin forms structurally heterogeneous amyloids that have been linked to type-2 diabetes. Thus, understanding the molecular interactions governing amylin...
Human amylin forms structurally heterogeneous amyloids that have been linked to type-2 diabetes. Thus, understanding the molecular interactions governing amylin aggregation can provide mechanistic insights in its pathogenic formation. Here, we demonstrate that fibril formation of amylin is altered by synthetic amphipathic copolymer derivatives of the styrene-maleic-acid (SMAQA and SMAEA). High-speed AFM is used to follow the real-time aggregation of amylin by observing the rapid formation of de novo globular oligomers and arrestment of fibrillation by the positively-charged SMAQA. We also observed an accelerated fibril formation in the presence of the negatively-charged SMAEA. These findings were further validated by fluorescence, SOFAST-HMQC, DOSY and STD NMR experiments. Conformational analysis by CD and FT-IR revealed that the SMA copolymers modulate the conformation of amylin aggregates. While the species formed with SMAQA are α-helical, the ones formed with SMAEA are rich in β-sheet structure. The interacting interfaces between SMAEA or SMAQA and amylin are mapped by NMR and microseconds all-atom MD simulation. SMAEA displayed π-π interaction with Phe23, electrostatic π-cation interaction with His18 and hydrophobic packing with Ala13 and Val17; whereas SMAQA showed a selective interaction with amylin's C terminus (residues 31-37) that belongs to one of the two β-sheet regions (residues 14-19 and 31-36) involved in amylin fibrillation. Toxicity analysis showed both SMA copolymers to be non-toxic in vitro and the amylin species formed with the copolymers showed minimal deformity to zebrafish embryos. Together, this study demonstrates that chemical tools, such as copolymers, can be used to modulate amylin aggregation, alter the conformation of species.
Topics: Amyloid; Animals; Computer Simulation; Diabetes Mellitus, Type 2; Fluorescence; Humans; Hydrophobic and Hydrophilic Interactions; Islet Amyloid Polypeptide; Maleates; Molecular Conformation; Protein Aggregates; Spectroscopy, Fourier Transform Infrared; Styrene; Styrenes; Zebrafish
PubMed: 34883118
DOI: 10.1016/j.jmb.2021.167385 -
Physiology & Behavior Jul 2010Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a... (Review)
Review
Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a direct action at the area postrema (AP) via amylin receptors that are heterodimers of the calcitonin receptor core protein with a receptor activity modifying protein. Peripheral amylin leads to accumulation of cyclic guanosine monophosphate, phosphorylated extracellular-signal regulated kinase 1/2 and c-Fos protein in AP neurons. The particular amylin-activated AP neurons mediating its anorexigenic action seem to be noradrenergic. The central pathways mediating amylin's effects have been characterized by lesioning and tracing studies, identifying important connections from the AP to the nucleus of the solitary tract and lateral parabrachial nucleus. Amylin was shown to interact, probably at the brainstem, with other signals involved in the short term control of food intake, namely cholecystokinin, glucagon-like peptide 1 and peptide YY. Amylin also interacts with the adiposity signal leptin; this interaction, which is thought to involve the hypothalamus, may have important implications for the development of new and improved hormonal obesity treatments. In conclusion, amylin actions on food intake seem to reside primarily within the brainstem, and the associated mechanisms are starting to be unraveled. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
Topics: Amyloid; Animals; Anorexia; Appetite Depressants; Brain Stem; Eating; Humans; Islet Amyloid Polypeptide; Neurons; Signal Transduction
PubMed: 20226802
DOI: 10.1016/j.physbeh.2010.03.001 -
Postepy Higieny I Medycyny... Mar 2015In patients or animals affected by type 2 diabetes mellitus (DM2, non-insulin dependent diabetes mellitus [NIDDM]), some pathological deposits, called amyloid, are... (Review)
Review
In patients or animals affected by type 2 diabetes mellitus (DM2, non-insulin dependent diabetes mellitus [NIDDM]), some pathological deposits, called amyloid, are observed among cells of islets of Langerhans. Among other constituents, the deposits consist of an insoluble, fibrillar form of polypeptide neurohormone called amylin, produced by pancreatic beta cells. It is thought that formation of fibrillar deposits of misfolded and aggregated polypeptide is highly toxic to beta cells and leads to cell dysfunction, cell loss, pancreas destruction and progress of the disease. Due to the extreme insolubility of this polypeptide and its instant fibrillation, amylin constitutes a methodological problem, and there is a need for a special methodology in experiments. Some mechanisms and factors that govern amylin fibrillization are rather poorly understood. This article presents amylin as a fibrillating molecule and some methods and methodological aspects and problems that emerge at successive steps during the fibrillation process, including hypothesized cytotoxicity mechanisms of this polypeptide.
Topics: Amyloid; Animals; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Islets of Langerhans; Pancreatic Polypeptide
PubMed: 25748622
DOI: 10.5604/17322693.1143050 -
Lancet (London, England) Dec 2021
Topics: Body Weight; Eating; Humans; Islet Amyloid Polypeptide; Weight Loss
PubMed: 34798059
DOI: 10.1016/S0140-6736(21)01999-1 -
Nature Jul 1989
Topics: Amyloid; Islet Amyloid Polypeptide
PubMed: 2747794
DOI: 10.1038/340272b0 -
Journal of Alzheimer's Disease : JAD 2018Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar... (Review)
Review
Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint.
Topics: Alzheimer Disease; Amino Acid Sequence; Cognition; Cognitive Dysfunction; Humans; Islet Amyloid Polypeptide; Neuroprotective Agents; Oxidative Stress; Treatment Outcome
PubMed: 30282360
DOI: 10.3233/JAD-180433 -
British Journal of Pharmacology Jun 2016Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin... (Review)
Review
Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA-approved drug used in insulin-requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin-mimetic compounds. Given that amylin-mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin. This is largely due to the unfavourable aggregative and solubility properties of the native peptide sequence, which are further complicated by the composition of amylin receptors. These are complexes of the calcitonin receptor with receptor activity-modifying proteins. This review explores what is known of the structure-function relationships of amylin and provides insights that can be drawn from the closely related peptide, CGRP. We also describe how this information is aiding the development of more potent and stable amylin mimetics, including peptide hybrids.
Topics: Amylin Receptor Agonists; Animals; Drug Design; Humans; Islet Amyloid Polypeptide; Receptors, Islet Amyloid Polypeptide; Structure-Activity Relationship
PubMed: 27061187
DOI: 10.1111/bph.13496 -
Cellular and Molecular Life Sciences :... Jun 2012Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and... (Review)
Review
Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.
Topics: Adiposity; Animals; Anti-Obesity Agents; Brain Stem; Energy Metabolism; Female; Gastric Emptying; Homeostasis; Humans; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Mice; Obesity; Rats; Receptors, Islet Amyloid Polypeptide; Satiation
PubMed: 22193913
DOI: 10.1007/s00018-011-0905-1 -
Nature Communications Feb 2022Social animals actively engage in contact with conspecifics and experience stress upon isolation. However, the neural mechanisms coordinating the sensing and seeking of...
Social animals actively engage in contact with conspecifics and experience stress upon isolation. However, the neural mechanisms coordinating the sensing and seeking of social contacts are unclear. Here we report that amylin-calcitonin receptor (Calcr) signaling in the medial preoptic area (MPOA) mediates affiliative social contacts among adult female mice. Isolation of females from free social interactions first induces active contact-seeking, then depressive-like behavior, concurrent with a loss of Amylin mRNA expression in the MPOA. Reunion with peers induces physical contacts, activates both amylin- and Calcr-expressing neurons, and leads to a recovery of Amylin mRNA expression. Chemogenetic activation of amylin neurons increases and molecular knockdown of either amylin or Calcr attenuates contact-seeking behavior, respectively. Our data provide evidence in support of a previously postulated origin of social affiliation in mammals.
Topics: Animals; Behavior, Animal; Female; Gene Knockout Techniques; Islet Amyloid Polypeptide; Mice; Preoptic Area; RNA, Messenger; Receptors, Calcitonin; Receptors, Islet Amyloid Polypeptide; Signal Transduction; Social Behavior
PubMed: 35136064
DOI: 10.1038/s41467-022-28131-z -
Mass Spectrometry Reviews May 2023Amylin (islet amyloid polypeptide [IAPP]) is a neuroendocrine hormone synthesized with insulin in the beta cells of pancreatic islets. The two hormones act in different... (Review)
Review
Amylin (islet amyloid polypeptide [IAPP]) is a neuroendocrine hormone synthesized with insulin in the beta cells of pancreatic islets. The two hormones act in different ways: in fact insulin triggers glucose uptake in muscle and liver cells, removing glucose from the bloodstream and making it available for energy use and storage, while amylin regulates glucose homeostasis. Aside these positive physiological aspects, human amyloid polypeptide (hIAPP) readily forms amyloid in vitro. Amyloids are aggregates of proteins and in the human body amyloids are considered responsible of the development of various diseases. These aspects have been widely described and discussed in literature and to give a view of the highly complexity of this biochemical behavior the different physical, chemical, biological and medical aspects are shortly described in this review. It is strongly affected by the presence on metal ions, responsible for or inhibiting the formation of fibrils. Mass spectrometry resulted (and still results) to be a particularly powerful tool to obtain valid and effective experimental data to describe the hIAPP behavior. Aside classical approaches devoted to investigation on metal ion-hIAPP structures, which reflects on the identification of metal-protein interaction site(s) and of possible metal-induced conformational changes of the protein, interesting results have been obtained by ion mobility mass spectrometry, giving, on the basis of collisional cross-section data, information on both the oligomerization processes and the conformation changes. Laser ablation electrospray ionization-ion mobility spectrometry-mass spectrometry (LAESI-IMS-MS), allowed to obtain information on the binding stoichiometry, complex dissociation constant, and the oxidation state of the copper for the amylin-copper interaction. Alternatively to inorganic ions, small organic molecules have been tested by ESI-IMS-MS as inhibitor of amyloid assembly. Also in this case the obtained data demonstrate the validity of the ESI-IMS-MS approach as a high-throughput screen for inhibitors of amyloid assembly, providing valid information concerning the identity of the interacting species, the nature of binding and the effect of the ligand on protein aggregation. Effects of Cu and Zn ions in the degradation of human and murine IAPP by insulin-degrading enzyme were studied by liquid chromatography/mass spectrometry (LC/MS). The literature data show that mass spectrometry is a highly valid and effective tool in the study of the amylin behavior, so to individuate medical strategies to avoid the undesired formation of amyloids in in vivo conditions.
Topics: Mice; Humans; Animals; Islet Amyloid Polypeptide; Copper; Spectrometry, Mass, Electrospray Ionization; Amyloid; Glucose; Insulins
PubMed: 34558100
DOI: 10.1002/mas.21732