islet amyloid polypeptide: structure, function, and pathophysiology

e model shar, several of the general features of the NMR and fragment, key dierence between the EPR based model and the others, A with respect to each other in the EPR mo, the staggered relationship leads to a le-handed twist. Yet despite extensive investigation, the biological significance of this is not fully understood. The correlation between in vitro biophysical studies using model membranes and in vivo toxicity is not clear and caution needs to be employed when extrapolating from biophysical studies that utilize simple model membranes to the in vivo environment. Asn to Leu mutants offer a nice example of the value of using isosteric substitutions. It is Islet amyloid polypeptide. The 1–19 fragments of both peptides adopt similar α-helical structures in the presence of detergent micelles, but they bind to micelle in different orientations [93, 95]. The biologically active sequences all contain a disulfide bridge between Cys-2 and Cys-7 and have an amidated C-terminus. This work was supported by a grant from the United States National Institutes of Health, GM078114, to Daniel P. Raleigh, Zachary Ridgway was supported in part by an NIH training Grant 5T32GM09271405, and Amy G. Wong by a GAANN fellowship from the Department of Education. B. Hyaline degeneration of the islands of Langerhans, Sim, and K. B. M. Reid, “Purication and c, insulin in the B cell secretory granules of the human pancr, cosecretion of islet amyloid polypeptide and insulin b, [] M. Stridsberg, S. Sandler, and E. Wila, levels of islet amyloid polypeptide in young with new-on, acid residues linked to amyloid bril forma, the National Academy of Sciences of the United States o, variations aect the kinetics and thermodynamics of am, formation: peptide models of pancreatic amyloid, divergence in a specic region of islet am, islet amyloid polypeptide in amyloid forma. 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]. A growing body of evidence suggests that β-cell failure in type 2 diabetes correlates with the formation of pancreatic islet amyloid deposits, indicating that islet amyloid may have an important role in β-cell loss in this disease. hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. Model membranes made up of the phospholipids found in β-cell membranes, but lacking cholesterol, also accelerate hIAPP amyloid formation, as do anionic model membranes that are capable of forming lipid rafts [110–112]. 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. hIAPP is a relatively hydrophobic polypeptide but contains several positively charged residues, Lys-1, Arg-11, and, depending upon the pH, His-18 (Figure 1). The S20G mutation has been described as pathological related, and G33R mutation may have a deleterious effect. The data presented here also propitiate new therapy opportunities, whether creating more effective drugs to diabetes or implementing a specific treatment to the patients with these mutations. A nonamyloidogenic analog of human IAPP, denoted by Pramlintide, in which residues 25, 28, and 29 were replaced by proline is approved by the FDA for use in type-1 and type-2 diabetes [170, 171]. human islet amyloid polypeptide transgenic mice, important in diseases outside the brain—lessons from the islets, “Cholesterol modulates the interaction of the islet amyloid. Amide H/D exchange rates are sensitive to H-bonding and have recently been used to study amide proton solvent protection in hIAPP amyloid fibrils. In this review, we discuss several fluorescence-based techniques including fluorescence/Förster resonance energy transfer (FRET), homo-FRET, fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), fluorescence lifetime imaging (FLIM), and photobleaching image correlation spectroscopy (pbICS) that are routinely used to identify protein oligomers in extracellular and intracellular matrices. As previously noted, hIAPP contains a large number of Asn residues and the kinetics of amyloid formation are sensitive to isosteric Asn to Leu substitutions. The Asn14Leu and Asn21Leu mutants did not form amyloid on the experimental timescale of these studies. IAPP interacts significantly more strongly with model membranes that contain a high fraction of anionic lipids. A systematic examination of the role of different Asn residues in hIAPP in amyloid formation and assembly has also been reported [30]. Primates and cats have been reported to form islet amyloid while, rodents, and dogs do not. NMR studies of a nonphysiological variant of hIAPP with a free C-terminal carboxyl group provided evidence for intermolecular interactions involving His-18 and Tyr-37 at pH 5.5 and it was suggested that these interactions play a role in the early stages of amyloid formation by hIAPP. Open questions in the field include the relative importance of the various mechanisms of Studies on intact hIAPP also indicate that the 20–29 segment is not the sole amyloidogenic determinant. By applying biophysical methods such as Thioflavin T fluorescence spectroscopy, fluorescence anisotropy, total reflection Fourier-transform infrared spectroscopy, circular dichroism spectroscopy and atomic force microscopy we analyse and compare their inhibition mechanism. Bell, C. Sample, A. H. Rubenstein, and D. F. Steiner, “An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing,”, L. Marzban, G. Trigo-Gonzalez, and C. B. Verchere, “Processing of pro-islet amyloid polypeptide in the constitutive and regulated secretory pathways of, A. Lukinius, E. Wilander, G. T. Westermark, U. Engstrom, and P. Westermark, “Co-localization of islet amyloid polypeptide and insulin in the B cell secretory granules of the human pancreatic islets,”, S. E. Kahn, D. A. These important early studies led to the view that the ability of IAPP to form amyloid in vitro and in vivo is determined by the primary sequence in the 20–29 region; however the situation is more complex. hIAPP is aggressively amyloidogenic in vitro, but CGRP does not form amyloid. Furthermore, comparative analyses with pramlintide, an amylin drug analogue, allowed inferring the second α-helix maintenance may be related to the aggregation potential. X. Zhou, G. Rivas, and A. P. Minton, “Macromolecular crowding and confinement: biochemical, biophysical, and potential physiological consequences,”, Y. Wang, M. Sarkar, A. E. Smith, A. S. Krois, and G. J. Pielak, “Macromolecular crowding and protein stability,”, M. Sarkar, J. Lu, and G. J. Pielak, “Protein crowder charge and protein stability,”, M. Senske, L. Törk, B. The dibasic Lys-Arg pair at the C-terminus is removed by carboxypeptidase and the Gly acts as the nitrogen donor for amidation of the C-terminal Tyr by the peptidyl amidating monooxygenase complex (PAM). IAPP is a neuroendocrine hormone, which is produced by pancreatic β-cells and co-secreted with insulin, ... Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-residue peptide hormone which is co-secreted with insulin by β-cells in the pancreas, specifically, in the islet of Langerhans. Finally, we propose that two different self-assembled fibril-like forms of amylin can interact to form a new fibril-like amylin. , the molecular mechanism of amyloid formation The only natural mutation found in the mature sequence of hIAPP is a Ser to Gly missense mutation at position 20. Quantitative mutational studies of amyloid fibril stability and of the kinetics of amyloid formation are much more challenging than studies with soluble, monomeric, globular proteins. found in other recent review articles [, , , ]. Amylin is an endocrine hormone peptide that consists of 37 residues and is the main component of extracellular amyloid deposits found in the pancreas of most type 2 diabetes patients. It is worth bearing in mind that some transgenic mouse models have high copy numbers of the human IAPP gene and can produce high levels of hIAPP. Utilizing graphical description it is explained how a smart targeted nano-delivery system could promote β-cell growth and development by inducing the Wnt signaling pathway (inhibiting Gsk3β), inhibiting inflammasome (inhibiting NLRP3), and activating autophagic target points (protecting Atg3/Atg7 complex from oxidative stress) thereby might ameliorate the severity of T2D. The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. This study reveals, for the first time, that there are four self-assembled amylin forms that differ in the orientations of the side chains along the β-arch and are all derived from the two ssNMR models. in diet-induced obese rats: eects on food intake, body weight, composition, energy expenditure, and gene expr, [] J. (c) View rotated by 90° showing the arrangement of the two stacks as a ribbon diagram. Copyright © 2016 Rehana Akter et al. ese, include peptides comprised of residues –,  and even smaller fragments from the – region [–, Subsequent X-ray crystallographic structural studies with a, segment is not the sole amyloidogenic determinant. The process of human IAPP (hIAPP) self-association, and the intermediate structures formed as well as the interaction of hIAPP with membrane systems seem to be, at least to a major extent, responsible for the cytotoxicity. e biologically active sequences all con, be signicantly less amyloidogenic than huma, TPIESHQVEKR KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, -residue signal sequence is shown in italics; the N- and C-terminal, in this issue for coverage of other topics a, are described in other articles in this issue and have been, been published in recent years which provide addition, information on various aspects of the biology and biophysics, disease, but there is still much that is unclear. IAPP is coexpressed and cosecreted with insulin by pancreatic β-cells (21– 23). Tissue macrophages were present in all pancreatic sections and tissue distribution was similar in exocrine and endocrine areas. The net positive charge on the molecule is important for interactions with negatively charged, nonphysiological model membranes and for interactions with sulfated proteoglycans of the extracellular matrix. An alternative approach has employed the strategy of conjugating groups to hIAPP. The Structure of the IAPP Amyloid Fibril, been developed based upon solid state NMR studies, and on, X-ray diraction studies of microcrystals of small peptide, fragments of hIAPP which form steric zippers, of two symmetrically related columns of IAPP monomers, top of each other to generate a U-shaped st, sheets. Residues that differ from the human IAPP sequence are in italics and underlined. islet amyloid polypeptide bril formation, cell granule peptides aect human islet amyloid polypeptide, beta-cell granule peptides form heteromolecular complex. Asn side chains contain both a hydrogen bond donor and acceptor and are hence capable of forming networks of interpolypeptide hydrogen bonds. Unfavorable electrostatic interactions are also likely to arise from the N-terminus of IAPP. Our data could help to better understand the mutations influence in the wild-type amylin sequence, being a starting point for the evaluation and characterization of other variations. All rights reserved. This is of interest because Ser-28 and Ser-29 are located at the interface of the two symmetrically related columns of hIAPP monomers in the fibril structure and are involved in networks of hydrogen bonded interactions (Figure 3). Disulfide bond formation leads to mature IAPP (Figure 3). Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM. ProIAPP is processed in the Golgi and in the insulin secretory granule [7, 8]. The polypeptide can be prepared by solid phase peptide synthesis making such studies possible. The authors are grateful to Professors S. Zraika, S. Kahn, and M. Zanni for numerous helpful discussions. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproductio, a role. Collectively, T1DM and T2DM might be linked through amylin evolvability, and a better understanding of amyloidogenic evolvability might also reveal clues to therapeutic interventions for AD comorbid with T2DM. The amyloid component of T2DM is the 37-residue islet amyloid polypeptide (IAPP), also known as amylin, which aggregates and accumulates in the pancreas [2,3]. 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]. Synonyms for Islet amyloid polypeptide in Free Thesaurus. There are rigorous, well-established methods for determining the stability of soluble proteins, but this is not always the case for amyloids. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. Song, and D. P. Raleigh, “Amyloid formation by pro-islet amyloid polypeptide processing intermediates: examination of the role of protein heparan sulfate interactions and implications for islet amyloid formation in type 2 diabetes,”, H. Wang and D. P. Raleigh, “The ability of insulin to inhibit the formation of amyloid by pro-islet amyloid polypeptide processing intermediates is significantly reduced in the presence of sulfated glycosaminoglycans,”, E. T. A. S. Jaikaran and A. Clark, “Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology,”, R. L. Hull, G. T. Westermark, P. Westermark, and S. E. Kahn, “Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes,”, J. C. Hutton, “The internal pH and membrane potential of the insulin-secretory granule,”, S. B. P. Charge, E. J. P. De Koning, and A. Clark, “Effect of pH and insulin on fibrillogenesis of islet amyloid polypeptide in vitro,”, A. Abedini and D. P. Raleigh, “The role of His-18 in amyloid formation by human islet amyloid polypeptide,”, P. Westermark, Z.-C. Li, G. T. Westermark, A. Leckström, and D. F. Steiner, “Effects of beta cell granule components on human islet amyloid polypeptide fibril formation,”, S. Janciauskiene, S. Eriksson, E. Carlemalm, and B. Ahrén, “B cell granule peptides affect human islet amyloid polypeptide (IAPP) fibril formation in vitro,”, E. T. A. S. Jaikaran, M. R. Nilsson, and A. Clark, “Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation,”, J. L. Larson and A. D. Miranker, “The mechanism of insulin action on islet amyloid polypeptide fiber formation,”, J. D. Knight, J. Of particular note, the rat sequence contains three Pro residues at positions 25, 28, and 29, while the human sequence has none (Figure 1). Anionic model membranes promote hIAPP amyloid formation in vitro and more highly charged systems have a larger effect for experiments conducted at high peptide to lipid ratios [107]. Fluorescence-based spectroscopic and microscopic techniques are highly effective as compared to other techniques for the evaluation of protein oligomerization, organization, and dynamics. , vol. Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. IAPP amyloid deposition has been correlated with disease severity, reduced β ‐cell mass, and the development of hyperglycemia. Human islet amyloid polypeptide (h-IAPP) is a peptide hormone that is synthesized and cosecreted with insulin from insulin-secreting pancreatic β-cells. of deamidated material in isolated islet am, challenge of characterizing the highly heterogeneous ensem-, residue plus the  possible deamidation pr, 5. Analysis of the role of the conserved disulfide in amyloid formation by human IAPP in homogenous and... Macrophages and pancreatic islet amyloidosis. Recent work also highlights a role for hIAPP aggregation and hyperamylinemia in cardiovascular complications of diabetes [16, 127]. It is not possible to cover all topics and all of the recent developments in IAPP research in a limited review and the reader is referred to other articles in this issue for coverage of other topics and for alternative views. ... Islet amyloid polypeptide: structure, function, and pathophysiology. It is important to emphasize that both structures are models based on, and consistent with, separate sets of experimental data which are sufficient to constrain the models but not to completely define a precise, three-dimensional, high resolution structure. In particular, the rate amyloid formation is significantly accelerated with increasing salt and the effects depend on the choice of anion. For example, fiber formation is more strongly suppressed in cell culture medium than in aqueous buffer. e Leu side chain has appr, the data than would experiments involving less co, nongenetically coded amino acids. Asn deamidation has been shown to accelerate hIAPP amyloid formation in vitro and to lead to changes in the morphology of hIAPP amyloid fibrils [47]. However, coformulation is also difficult in this case because of the poor solubility of hIAPP and Pramlintide. -, and δ. In some cases, amyloid fibril deposits disrupt tissue and can lead to organ failure, but, in most cases, activation of overlapping cellular mechanisms and downstream signaling pathways are believed to lead to toxicity. Given the analogous cellular stress environments shared by both T2DM and AD, the objective of this study is to explore T2DM pathogenesis from the viewpoint of amyloidogenic evolvability. 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. We discovered that fibers are nontoxic if they are washed free of adsorbed nonfibrillar components. 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. Pro is highly energetically unfavorable in a β-sheet and is a well-known disrupter of secondary structure. In addition, Ser-19 and Ser-20 are highly conserved in known IAPP sequences and Ser-34 are strictly conserved, making them interesting targets for future analysis (Figure 1). A loop should be able to accommodate mutations, making it unclear why mutations in this region have such a dramatic impact on amyloid formation. hIAPP adopts a helix-kink-helix structure on model membranes with the helices located between residues 5 to 17 and 20 to 27. Processing of human PreProIAPP to produce mature IAPP. Although amyloid formation was previously shown to be catalyzed by both synthetic and chloroform-extracted phospholipid surfaces, it is instead inhibited by membrane surfaces prepared directly from the plasma membranes of an immortal β-cell line. Extracellular accumulation of this peptide results in damage to insulin-producing β cell membranes and cell death. Comparison of the rat/mouse sequence to the sequence of hIAPP, together with early in vitro experiments, appeared to confirm the hypothesis that the ability to form amyloid is controlled by the identity of the 20–29 segment [20, 21]. 2DIR line widths are sensitive to local dynamics and can be combined with molecular dynamics simulations to probe protein structure. Multiple studies point to the importance of the peptide’s interaction with biological membranes and the cytotoxicity of hIAPP species. Animal studies with food-matched, controls have led to the hypothesis that weight loss occurs via, leptin sensitivity [, , ]. e rst C-terminal cleavage leaves a Gly-L, tripeptide sequence as the new C-terminus. Marginal changes of the environment can severely affect the energy landscape of protein folding. The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. methyl modications in this region [–]. Additional fluorescence results indicate that 10 and 20% of cholesterol slightly slow down the kinetics of oligomer and fibril formation while anionic lipids accelerate this kinetics. Current progress fabricated in T2D research concerning intracellular signaling cascade, inflammasome, autophagy, genetic and epigenetics changes is discretely explained in simple terms. in the granule is noticeably lower than that of insulin, Soluble insulin is one of the most potent inhibitors of IAPP, aggregation; however insulin is in a semicrystalline state in, be on the order of  to  picomolar and to rise to  to , be much higher and this is the more relevant num, mediated, but are still not fully understood. His- in, analysis, this substitution is expected to destabilize the cross-, studies argue that the His- to Arg substi, of groups have independently examined the ro, signicantly slowed when the residue is pr, is also aected by the protonation state of the N-terminus, Linearized PB calculations may not be rigorously valid, details of the analysis should be interpreted with caution. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In contrast to the mouse studies, a recent investigation used a cultured transgenic islet model to show that secretion of IAPP is an important factor in β-cell toxicity and islet amyloid formation. Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Collectively, these different approaches demonstrate that there is considerable potential for the design of hIAPP therapeutics with improved properties. The serum component of the medium is responsible for this inhibition. in vitro In the fragment model, Ser-28 and Ser-29 are involved in a steric zipper and make extensive hydrogen bonding interactions [26]. Mechanistic studies of IAPP induced model membrane disruption are an active area of research and a variety of models have been proposed. -cells of the pancreatic islets of Langerhans. In rats, the circulating concentration of IAPP is reported to be on the order of 3 to 5 picomolar and to rise to 15 to 20 picomolar with elevation of blood glucose [4, 5]. e dibasic Lys-, and the Gly acts as the nitrogen donor for amidation of the, and is found in the halo region of the granule, while insulin. The final sequence, denoted by hIAPP, Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA, Diabetes Research Program, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA, Research Department of Structural and Molecule Biology, University College London, Gower Street, London WC1E 6BT, UK, E. L. Opie, “The relation of diabetes mellitus to lesions of the pancreas.

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