In Silico Studies of The Human IAPP In Presence of Osmolytes

Abstract The human islet amyloid polypeptide or amylin is secreted along with insulin by pancreatic islets. Under the drastic environmental conditions, amylin can aggregate to form amyloid fibrils. This amyloid plaque of hIAPP in the pancreatic cells is the cause of Type II diabetes. Early stages of amylin aggregates are more cytotoxic than the matured fibrils. Here, we have used the all-atom molecular dynamic simulation to see the effect of water, TMAO, urea and urea:TMAO having ratio 2:1 of different concentrations on the amylin protein. Our study suggest that the amylin protein forms β-sheets in its monomeric form and may cause the aggregation of protein through the residue 13-17 and the C-terminal region. α-helical content of protein increases with an increase in TMAO concentration by decreasing the SASA value of protein, increase in intramolecular hydrogen bonds and on making the short range hydrophobic interactions. Electrostatic potential surfaces shows that hydrophobic groups are buried and configurational entropy of backbone atoms is lesser in presence of TMAO, whereas opposite behaviour is obtained in case of urea. Counteraction effect of TMAO using Kast model towards urea is also observed in ternary solution of urea:TMAO.

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Hexafluoroisopropanol Induces Amyloid Fibrils of Islet Amyloid Polypeptide by Enhancing Both Hydrophobic and Electrostatic Interactions

Journal of Biological Chemistry ◽

10.1074/jbc.m111.226688 ◽

2011 ◽

Vol 286 (27) ◽

pp. 23959-23966 ◽

Cited By ~ 53

Author(s):

Kotaro Yanagi ◽

Mizue Ashizaki ◽

Hisashi Yagi ◽

Kazumasa Sakurai ◽

Young-Ho Lee ◽

...

Keyword(s):

Electrostatic Interactions ◽

Amyloid Fibrils ◽

Hydrophobic Interactions ◽

Islet Amyloid Polypeptide ◽

Helical Structure ◽

Thioflavin T ◽

General View ◽

Islet Amyloid ◽

Neutral Ph ◽

Low Concentrations

Although amyloid fibrils deposit with various proteins, the comprehensive mechanism by which they form remains unclear. We studied the formation of fibrils of human islet amyloid polypeptide associated with type II diabetes in the presence of various concentrations of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) under acidic and neutral pH conditions using CD, amyloid-specific thioflavin T fluorescence, fluorescence imaging with thioflavin T, and atomic force microscopy. At low pH, the formation of fibrils was promoted by HFIP with an optimum at 5% (v/v). At neutral pH in the absence of HFIP, significant amounts of amorphous aggregates formed in addition to the fibrils. The addition of HFIP suppressed the formation of amorphous aggregates, leading to a predominance of fibrils with an optimum effect at 25% (v/v). Under both conditions, higher concentrations of HFIP dissolved the fibrils and stabilized the α-helical structure. The results indicate that fibrils and amorphous aggregates are different types of precipitates formed by exclusion from water-HFIP mixtures. The exclusion occurs through the combined effects of hydrophobic interactions and electrostatic interactions, both of which are strengthened by low concentrations of HFIP, and a subtle balance between the two types of interactions determines whether the fibrils or amorphous aggregates dominate. We suggest a general view of how the structure of precipitates varies dramatically from single crystals to amyloid fibrils and amorphous aggregates.

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Supramolecular chirality in peptide microcrystals

Chemical Communications ◽

10.1039/c4cc05002a ◽

2015 ◽

Vol 51 (1) ◽

pp. 89-92 ◽

Cited By ~ 25

Author(s):

Dmitry Kurouski ◽

Joseph D. Handen ◽

Rina K. Dukor ◽

Laurence A. Nafie ◽

Igor K. Lednev

Keyword(s):

Amyloid Fibrils ◽

Human Islet ◽

Islet Amyloid ◽

Supramolecular Chirality ◽

Peptide Segments

VCD reveals supramolecular chirality in microcrystals of two peptide segments from human islet amyloid (IAPP, amylin). Previously such supramolecular chirality has been observed by VCD only for amyloid fibrils.

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Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

Biochemical Journal ◽

10.1042/bj20030852 ◽

2004 ◽

Vol 377 (3) ◽

pp. 709-716 ◽

Cited By ~ 67

Author(s):

Emma T. A. S. JAIKARAN ◽

Melanie R. NILSSON ◽

Anne CLARK

Keyword(s):

Type 2 Diabetes ◽

Amyloid Fibrils ◽

Secretory Granules ◽

Pancreatic Beta Cell ◽

Islet Amyloid Polypeptide ◽

Fibril Formation ◽

Islet Amyloid ◽

Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

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The interplay between lipids and dopamine on α-synuclein oligomerization and membrane binding

Bioscience Reports ◽

10.1042/bsr20130092 ◽

2013 ◽

Vol 33 (5) ◽

Cited By ~ 16

Author(s):

Chi L. L. Pham ◽

Roberto Cappai

Keyword(s):

Lipid Membranes ◽

Amyloid Fibrils ◽

Lipid Membrane ◽

Hydrophobic Interactions ◽

Membrane Integrity ◽

Lipid Vesicles ◽

Helical Conformation ◽

Unfolded Protein ◽

Natively Unfolded Protein ◽

Natively Unfolded

The deposition of α-syn (α-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). α-syn is a natively unfolded protein and adopts an α-helical conformation upon binding to lipid membrane. Oligomeric species of α-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, α-syn form of SDS-resistant soluble oligomers. It is postulated that the formation of the α-syn:DA oligomers involves the cross-linking of DA-melanin with α-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced α-syn oligomerization and studied the ability of α-syn:DA oligomers to interact with lipids vesicles. Our results show that the interaction of α-syn with lipids inhibits the formation of DA-induced α-syn oligomers. Moreover, the α-syn:DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of α-syn:DA oligomers may alter the actions of α-syn which require membrane association, leading to disruption of its normal cellular function.

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Islet Amyloid Polypeptide Forms Rigid Lipid–Protein Amyloid Fibrils on Supported Phospholipid Bilayers

Journal of Molecular Biology ◽

10.1016/j.jmb.2007.11.077 ◽

2008 ◽

Vol 376 (1) ◽

pp. 42-54 ◽

Cited By ~ 81

Author(s):

Yegor A. Domanov ◽

Paavo K.J. Kinnunen

Keyword(s):

Amyloid Fibrils ◽

Islet Amyloid Polypeptide ◽

Phospholipid Bilayers ◽

Islet Amyloid

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X-Ray Absorption Spectroscopy Measurements of Cu-ProIAPP Complexes at Physiological Concentrations

Condensed Matter ◽

10.3390/condmat4010013 ◽

2019 ◽

Vol 4 (1) ◽

pp. 13 ◽

Cited By ~ 5

Author(s):

Emiliano De Santis ◽

Emma Shardlow ◽

Francesco Stellato ◽

Olivier Proux ◽

Giancarlo Rossi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Absorption Spectroscopy ◽

Amyloid Fibrils ◽

High Energy ◽

Islet Amyloid ◽

X Ray ◽

X Ray Absorption

The amyloidogenic islet amyloid polypeptide (IAPP) and the associated pro-peptide ProIAPP1–48 are involved in cell death in type 2 diabetes mellitus. It has been observed that interactions of this peptide with metal ions have an impact on the cytotoxicity of the peptides as well as on their deposition in the form of amyloid fibrils. In particular, Cu(II) seems to inhibit amyloid fibril formation, thus suggesting that Cu homeostasis imbalance may be involved in the pathogenesis of type 2 diabetes mellitus. We performed X-ray Absorption Spectroscopy (XAS) measurements of Cu(II)-ProIAPP complexes under near-physiological (10 μM), equimolar concentrations of Cu(II) and peptide. Such low concentrations were made accessible to XAS measurements owing to the use of the High Energy Resolved Fluorescence Detection XAS facility recently installed at the ESRF beamline BM16 (FAME-UHD). Our preliminary data show that XAS measurements at micromolar concentrations are feasible and confirm that ProIAPP1–48-Cu(II) binding at near-physiological conditions can be detected.

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Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis

Journal of Diabetes Research ◽

10.1155/2015/515307 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Phuong Trang Nguyen ◽

Nagore Andraka ◽

Carole Anne De Carufel ◽

Steve Bourgault

Keyword(s):

Type Ii Diabetes ◽

Amyloid Fibrils ◽

Driving Forces ◽

Islet Amyloid Polypeptide ◽

Type Ii Diabetes Mellitus ◽

Major Protein ◽

Local Concentration ◽

Amyloid Formation ◽

Type Ii ◽

Islet Amyloid

Type II diabetes mellitus is associated with the deposition of fibrillar aggregates in pancreatic islets. The major protein component of islet amyloids is the glucomodulatory hormone islet amyloid polypeptide (IAPP). Islet amyloid fibrils are virtually always associated with several biomolecules, including apolipoprotein E, metals, glycosaminoglycans, and various lipids. IAPP amyloidogenesis has been originally perceived as a self-assembly homogeneous process in which the inherent aggregation propensity of the peptide and its local concentration constitute the major driving forces to fibrillization. However, over the last two decades, numerous studies have shown a prominent role of amyloid cofactors in IAPP fibrillogenesis associated with the etiology of type II diabetes. It is increasingly evident that the biochemical microenvironment in which IAPP amyloid formation occurs and the interactions of the polypeptide with various biomolecules not only modulate the rate and extent of aggregation, but could also remodel the amyloidogenesis process as well as the structure, toxicity, and stability of the resulting fibrils.

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Extended life span is associated with insulin resistance in a transgenic mouse model of insulinoma secreting human islet amyloid polypeptide

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00137.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. E418-E424 ◽

Cited By ~ 3

Author(s):

Sofianos Andrikopoulos ◽

Rebecca L. Hull ◽

C. Bruce Verchere ◽

Feng Wang ◽

Shani M. Wilbur ◽

...

Keyword(s):

Insulin Resistance ◽

Life Span ◽

Amyloid Fibrils ◽

Islet Amyloid Polypeptide ◽

Transgenic Animals ◽

Human Islet ◽

Amyloid Formation ◽

Islet Amyloid ◽

Glucose Levels ◽

Human Islet Amyloid Polypeptide

Pancreatic amyloid is found in patients with insulinomas and type 2 diabetes. To study mechanisms of islet amyloidogenesis, we produced transgenic mice expressing the unique component of human islet amyloid, human islet amyloid polypeptide (hIAPP). These mice develop islet amyloid after 12 mo of high-fat feeding. To determine whether we could accelerate the rate of islet amyloid formation, we crossbred our hIAPP transgenic animals with RIP-Tag mice that develop islet tumors and die at 12 wk of age from hypoglycemia. At 12 wk of age, this new line of hIAPP×RIP-Tag mice was heavier (29.7 ± 1.0 vs. 25.0 ± 1.3 g, P < 0.05) and had increased plasma glucose levels (4.6 ± 0.4 vs. 2.9 ± 0.6 mmol/l, P < 0.05) compared with littermate RIP-Tag mice. However, the hIAPP×RIP-Tag mice did not display islet amyloid or amyloid fibrils despite high circulating hIAPP levels (24.6 ± 7.0 pmol/l). Interestingly, hIAPP×RIP-Tag mice had a longer life span than RIP-Tag mice (121 ± 8 vs. 102 ± 5 days, P < 0.05). This increase in life span in hIAPP×RIP-Tag was positively correlated with body weight ( r = 0.48, P < 0.05) and was associated with decreased insulin sensitivity compared with RIP-Tag mice. hIAPP×RIP-Tag mice did not develop amyloid during their 4-mo life span, suggesting that increased hIAPP secretion is insufficient for islet amyloid formation within such a short time. However, hIAPP×RIP-Tag mice did have an increase in life span that was associated with insulin resistance, suggesting that hIAPP has extrapancreatic effects, possibly on peripheral glucose metabolism.

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