islet amyloid polypeptide: structure, function, and pathophysiology

This allows a simpler interpretation of the data than would experiments involving less conservative replacements. Caspase- in turn activates the, in islets and in cultured cells exposed to high concentrations, IAPP toxicity has also been proposed to result from, e eciency with which hIAPP permeabilizes membranes, depends on a range of factors including the lipid t, used model systems contain a much higher percentage of, and because gangliosides and cholesterol modula, membrane interactions [, ]. In Type 2 diabetes, TAPP converts into a beta-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Recently, we proposed that Alzheimer's disease (AD)-relevant amyloidogenic proteins (APs), such as amyloid-β (Aβ) and tau, might be involved in evolvability against diverse stressors in the brain. Pramlintide was designed based on comparison of the sequences of rat and human IAPP and is simply human IAPP with the three Pro substitutions found in the rat polypeptide. The islets of patients with type 2 diabetes (T2D) are characterized by the deposition of islet amyloid 1, 2 as well as β‐cell dysfunction 3.Human (h) islet amyloid polypeptide (IAPP), a 37 amino acid peptide, is co‐secreted with insulin from β‐cells and is a main component of islet amyloid deposits. Pro-hIAPP is cleaved by the prohormone convertases PC(1/3) and PC2 at two conserved dibasic sites, indicated by arrows. Islet amyloid polypeptide (TAPP), or 'amylin', is co-stored with insulin in secretory granules of pancreatic islet beta-cells. Fan, Z. Zhou et al., “The contrasting effect of macromolecular crowding on amyloid fibril formation,”, J. Seeliger, A. Werkmüller, and R. Winter, “Macromolecular crowding as a suppressor of human IAPP fibril formation and cytotoxicity,”, M. Gao, K. Estel, J. Seeliger et al., “Modulation of human IAPP fibrillation: cosolutes, crowders and chaperones,”, M. Gao and R. Winter, “The effects of lipid membranes, crowding and osmolytes on the aggregation, and fibrillation propensity of human IAPP,”, D. F. Kruger and M. A. Gloster, “Pramlintide for the treatment of insulin-requiring diabetes mellitus: rationale and review of clinical data,”, R. E. Ratner, R. Dickey, M. Fineman et al., “Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial,”, F. D. Allard, A. E. Wallace, and C. J. Greenbaum, “Emerging therapies: going beyond insulin in treating individuals with type 1 diabetes mellitus,”, H. E. Lebovitz, “Adjunct therapy for type 1 diabetes mellitus,”, K. G. Sam and G. Tungha, “Emergence of promising therapies in diabetes mellitus,”, J. D. Roth, B. L. Roland, R. L. Cole et al., “Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies,”, H. Wang, A. Abedini, B. Ruzsicska, and D. P. Raleigh, “Rationally designed, nontoxic, nonamyloidogenic analogues of human islet amyloid polypeptide with improved solubility,”, R. Kowalczyk, M. A. Brimble, Y. Tomabechi, A. J. Fairbanks, M. Fletcher, and D. L. Hay, “Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure–activity relationships for amylin receptor agonism,”, M. F. A. N. Guterres, L. H. Guerreiro, B. Melo-Ferreira, L. C. S. Erthal, and L. M. T. R. Lima, “Amylin conjugation with methoxyl polyethyleneglycol,”, L.-M. Yan, A. Velkova, M. Tatarek-Nossol et al., “Selectively N-methylated soluble IAPP mimics as potent IAPP receptor agonists and nanomolar inhibitors of cytotoxic self-assembly of both IAPP and A, A. Velkova, M. Tatarek-Nossol, E. Andreetto, and A. Kapurniotu, “Exploiting cross-amyloid interactions to inhibit protein aggregation but not function: nanomolar affinity inhibition of insulin aggregation by an IAPP mimic,”. The importance of electrostatic interactions in hIAPP amyloid is also reflected in the dependence of the kinetics of hIAPP amyloid formation on ionic strength and on the type of salt. The polypeptide can be prepared by solid phase peptide synthesis making such studies possible. The first C-terminal cleavage leaves a Gly-Lys-Arg tripeptide sequence as the new C-terminus. assembly domain within the islet amyloid polypeptide, the recognition interface between the islet amyloid polypep, interaction interface as high-anity binding sit, amyloid brils by prol ine mutations outside of the putative amy-, loidogenic domain: is there a critical am, alence in the brillar assembly of islet amyloid pol, and bioactive human islet amyloid polypeptide (I, Proceedings of the National Academy of Sciences of the United, islet amyloid polypeptide aggregation: revealing the polymo. These residues are outside of the ordered amyloid core in both the NMR and X-ray models, but they might still affect the stability of the amyloid fibers. Amylin is a 37-amino acid cytotoxic constituent of amyloid deposits found in the islets of Langerhans of patients with type NMR based structures of IAPP fragments and of full, reported [–]. There is also interest in combining leptin and hIAPP for the treatment of obesity [175]. We suggest that channel formation may be the mechanism of cytotoxicity of human amylin. The site of initiation of amyloid formation in vivo is controversial. Soluble insulin is one of the most potent inhibitors of IAPP aggregation and may play a role in modulating intragranule aggregation; however insulin is in a semicrystalline state in the granule [71–75]. e rst  amino acids constitute the signal sequence, process. It is not known if perlecan is associated with islet amyloid because in vivo amyloid fibers are long-lived structures that present HSPG binding sites, or because HSPGs directly promote amyloid formation, but it is well documented that the glycosaminoglycan (GAG) chains of HSPGs catalyze hIAPP amyloid formation in vitro [64, 104]. Islet amyloid ¢brils are formed from islet amyloid polypeptide (IAPP), also known as ‘amylin’, which is a 37 amino acid peptide co-secreted with insulin from the L-cells of pancreatic islets in both diabetic and non-a¡ected subjects [3^6]. The results are consistent with an extracellular origin of islet amyloid. However other studies wi, some transgenic mouse models have high copy numbers of, used a cultured transgenic islet model to show that secretion, increased IAPP secretion but did not increase the amoun, extracellular origin of islet amyloid. The hormone is also involved in controlling satiety and acts as an adiposity signal [80–82]. -cell death are not fully defined. The ability of cow, bear, and puffer fish IAPP to form amyloid have not been investigated. The Physical Chemical Properties of IAPP, and the Importance of the 20–29 Region in, tains several positively charged residues, L, depending upon the pH, His- (Figure ). -cell death, the relevance of reductionist biophysical studies to the situation Mitochondrial membranes, which are unique in their lipid composition, are proposed as prime targets for the early intracellular formation of hIAPP toxic entities. Monomeric hIAPP does not fold to a compact globular structure and can be classified as an intrinsically disordered protein, but it is not a random coil. Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 D... Islet amyloid polypeptide (IAPP;Amylin) influences the endocrine but not the exocrine rat pancreas. Under such conditions the suppressive effect of proline was decreased, whereas the pharmacological chaperone remains active. The location of the transient β-sheet offers an explanation for the sensitivity of IAPP amyloid formation to some of the substitutions within the 20–29 region [44]. These include identifying the initiation site(s) of amyloid formation in vivo; defining the nature of the toxic species; elucidating the mechanisms of islet amyloid formation in vivo and in vitro; understanding the mechanisms of β-cell death; defining the mechanisms of hIAPP clearance in vivo and the role such processes may play in IAPP toxicity. Type 2 diabetes (T2D) is a common protein misfolding disease (PMD), and its pathogenesis is considered to be tightly associated with the aggregation of the disease-causative hIAPP (or amylin). The six Asn residues in hIAPP render the molecule susceptible to deamidation. II diabetes. Deamidation has also been shown to promote amyloid formation by otherwise nonamyloidogenic peptide fragments of hIAPP [48]. hIAPP is aggressively amyloidogenic in vitro, but CGRP does not form amyloid. Independent amide H/D exchange measurements and two-dimensional infrared (2DIR) studies are largely consistent with the NMR model. The concentration of IAPP in the granule is noticeably lower than that of insulin, about 1%-2% of the insulin level, but it is still much higher than that required to promote rapid amyloid formation in vitro [66, 67]. However, the local concentration after release from the granule will be much higher and this is the more relevant number for amyloid formation. In the solid state NMR model, the N-terminal strand, encompasses residues  to  and the C-terminal strand, the NMR model in the location of the C-terminal, it places residues  to  in the C-terminal, which are consistent with the experimental restrain, major dierences between the two are the register of the, side chains. hIAPP contains three aromatic residues: Phe-15, Phe-23, and Tyr-37. The process of fiber growth at the membrane surface can contribute to membrane disruption in some cases, while other studies have shown that formation of β-structure is not required to disrupt membranes [149, 151–156]. Ferret and porcine IAPP are reported to be significantly less amyloidogenic than human IAPP. A systematic examination of the role of different Asn residues in hIAPP in amyloid formation and assembly has also been reported [30]. Interest in islet amyloid has undergone resurgence due to the realization that β-cell dysfunction and death and the loss of β-cell mass are key features of T2D [117, 118]. Our data suggest amylin, a secretory product of pancreatic B-cells, as a peptide with strong paracrine effects within the Langerhans islet. His-18 in hIAPP is replaced by Arg in rIAPP and, based upon the PB analysis, this substitution is expected to destabilize the cross-β structure. © 2008-2021 ResearchGate GmbH. So far, four different molecular structures of the self-assembled amylin fibrils have been observed experimentally: two ssNMR models and two crystal models. Islet amyloid is found in the degu, a rodent, but it is derived from insulin, not from IAPP. IAPP amyloid deposition has been correlated with disease severity, reduced β ‐cell mass, and the development of hyperglycemia. Copyright © 2016 Rehana Akter et al. The aggregation of such proteins either in the intracellular context or extracellular matrix is associated with several adverse pathophysiological conditions such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, Spinocerebellar ataxia, and Type-II diabetes.

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