Membrane interaction of islet amyloid polypeptide

Jayasinghe, Sajith; Langen, Ralf

doi:10.1016/j.bbamem.2007.01.022

Cited by 166 publications

(208 citation statements)

References 86 publications

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“…The importance of postion-18 is consistent with NMR studies of IAPP fragments in the presence of model membranes (45). hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and rIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] , which differ only in the identity of residue-18, bind membranes in different orientations, and these differences are believed to correlate with the difference in the potential for membrane disruption (45,46). In summary, our data dissociate IAPP-induced leakage of standard model membranes from direct cellular toxicity, thereby indicating that further studies to identify the precise mechanism (s) of IAPP cellular toxicity are essential for the optimal development of therapeutic strategies to prevent T2D and islet graft failure.…”

Section: Discussionsupporting

confidence: 65%

“…Membrane disruption has attracted considerable interest, and a range of studies have examined interactions of IAPP with model membranes. Vesicles containing a significant fraction of anionic lipids accelerate amyloid formation by IAPP in vitro, and human IAPP (hIAPP) induces membrane leakage in these systems (14)(15)(16)(17). This has led to the hypothesis that membrane leakage may be a critical factor in islet amyloidosis cytotoxicity, but the relationship between studies with model membranes and in vivo or in vitro toxicity are not clear, especially as the β-cell membrane differs significantly from standard model membranes.…”

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confidence: 99%

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Islet amyloid polypeptide toxicity and membrane interactions

Cao

Abedini

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

131

143

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Islet amyloid polypeptide (IAPP) is responsible for amyloid formation in type 2 diabetes and contributes to the failure of islet cell transplants, however the mechanisms of IAPP-induced cytotoxicity are not known. Interactions with model anionic membranes are known to catalyze IAPP amyloid formation in vitro. Human IAPP damages anionic membranes, promoting vesicle leakage, but the features that control IAPP-membrane interactions and the connection with cellular toxicity are not clear. Kinetic studies with wildtype IAPP and IAPP mutants demonstrate that membrane leakage is induced by prefibrillar IAPP species and continues over the course of amyloid formation, correlating additional membrane disruption with fibril growth. Analyses of a set of designed mutants reveal that membrane leakage does not require the formation of β-sheet or α-helical structures. A His-18 to Arg substitution enhances leakage, whereas replacement of all of the aromatic residues via a triple leucine mutant has no effect. Biophysical measurements in conjunction with cytotoxicity studies show that nonamyloidogenic rat IAPP is as effective as human IAPP at disrupting standard anionic model membranes under conditions where rat IAPP does not induce cellular toxicity. Similar results are obtained with more complex model membranes, including ternary systems that contain cholesterol and are capable of forming lipid rafts. A designed point mutant, I26P-IAPP; a designed double mutant, G24P, I26P-IAPP; a double N-methylated variant; and pramlintide, a US Food and Drug Administration-approved IAPP variant all induce membrane leakage, but are not cytotoxic, showing that there is no one-to-one relationship between disruption of model membranes and induction of cellular toxicity.

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Islet amyloid polypeptide toxicity and membrane interactions

Cao

Abedini

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

131

143

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“…These include genetic predisposition in occasional families with mutations leading to increased amyloidogenicity of the amyloid protein (8) and reproduction of the disease phenotype in rodent models transgenic for the relevant human amyloidogenic protein (9). There is an increasing appreciation that the cytotoxic forms of amyloidogenic proteins are small nonfibrillar oligomers that may form in membranes and cause nonselective membrane permeability (7,10,11), the toxic oligomer hypothesis. Moreover, misfolding and aggregation of amyloidogenic proteins into toxic oligomers induce apoptosis through the mechanism of endoplasmic reticulum stress (ER stress) (12,13).…”

Section: Hyperglycemia In Type 2 Diabetes Mellitus (T2dm)mentioning

confidence: 99%

Calcium-activated Calpain-2 Is a Mediator of Beta Cell Dysfunction and Apoptosis in Type 2 Diabetes

Huang

Gurlo

Haataja

et al. 2010

Journal of Biological Chemistry

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The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca 2؉ -sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca 2؉ and hyperactivation of calpain-2. Cleavage of ␣-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca 2؉ -calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM. Hyperglycemia in type 2 diabetes mellitus (T2DM)3 is due to impaired insulin secretion in the setting of relative insulin resistance (1). The islets of Langerhans in T2DM are characterized by a deficit in beta cells, increased beta cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP), a 37-amino acid highly conserved peptide co-expressed and secreted with insulin by pancreatic beta cells (2, 3).The pathology of the islet in T2DM and brain in neurodegenerative diseases such as Alzheimer disease share several parallels. In both, the loss of functional tissue is associated with deposition of a locally expressed protein with the potential to form amyloid fibrils (Alzheimer beta protein in Alzheimer disease and IAPP in T2DM) (2, 4). In both T2DM and Alzheimer disease, there has been a debate as to whether the amyloid deposits contribute to cell loss (the so-called amyloid hypothesis) or are secondary to the processes leading to cell loss. Evidence against a direct role of amyloid deposits on cell loss is the poor correlation between the extent of amyloid deposits and the severity of disease in both human and animal models (3,5,6). Moreover, preformed amyloid fibrils are not cytotoxic when applied to cells (7).However, several lines of evidence are supportive of a role of cytotoxicity by amyloidogenic proteins. These include genetic predisposition in occasional families with mutations leading to increased amyloidogenicity of the amyloid protein (8) and reproduction of the disease phenotype in rodent models transgenic for the relevant human amyloidogenic protein (9). There is an increasing appreciation that the cytotoxic forms of amyloidogenic proteins are small nonfibrillar oligomers that may form in membranes and cause nonselective membrane permeability (7, 10, 11), the toxic oligomer hypothesis. Moreover, misfolding and aggregation of amyloidogenic proteins into toxic oligomers induce apoptosis through the mechanism of endoplasmic retic...

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“…The endocrine hormone amylin (also known as islet amyloid polypeptide) appears to have key roles in diabetes pathology (3)(4)(5). The normal functions of amylin include the inhibition of glucagon secretion, slowing down the emptying of the stomach, and inducing a feeling of satiety through the actions of the hormone on neurons of the hypothalamus in the brain (5).…”

mentioning

confidence: 99%

“…One of the hallmarks of type 2 diabetes, found in 90% of patients, is the formation of extracellular amyloid aggregates composed of amylin (3)(4)(5). The amyloid deposits accumulate in the interstitial fluid between islet cells and are usually juxtaposed with the ␤-cell membranes (3).…”

mentioning

confidence: 99%

Dynamic α-Helix Structure of Micelle-bound Human Amylin

Patil

Sheftic

et al. 2009

Journal of Biological Chemistry

176

219

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Amylin is an endocrine hormone that regulates metabolism. In patients afflicted with type 2 diabetes, amylin is found in fibrillar deposits in the pancreas. Membranes are thought to facilitate the aggregation of amylin, and membrane-bound oligomers may be responsible for the islet ␤-cell toxicity that develops during type 2 diabetes. To better understand the structural basis for the interactions between amylin and membranes, we determined the NMR structure of human amylin bound to SDS micelles. The first four residues in the structure are constrained to form a hairpin loop by the single disulfide bond in amylin. The last nine residues near the C terminus are unfolded. The core of the structure is an ␣-helix that runs from about residues 5-28. A distortion or kink near residues 18 -22 introduces pliancy in the angle between the N-and C-terminal segments of the ␣-helix. Mobility, as determined by 15 N relaxation experiments, increases from the N to the C terminus and is strongly correlated with the accessibility of the polypeptide to spin probes in the solution phase. The spin probe data suggest that the segment between residues 5 and 17 is positioned within the hydrophobic lipid environment, whereas the amyloidogenic segment between residues 20 and 29 is at the interface between the lipid and solvent. This orientation may direct the aggregation of amylin on membranes, whereas coupling between the two segments may mediate the transition to a toxic structure. Type 2 diabetes affects over 100 million people worldwide (1) and is thought to cost upward of $130 billion dollars a year to treat in the United States alone (2). The endocrine hormone amylin (also known as islet amyloid polypeptide) appears to have key roles in diabetes pathology (3-5). The normal functions of amylin include the inhibition of glucagon secretion, slowing down the emptying of the stomach, and inducing a feeling of satiety through the actions of the hormone on neurons of the hypothalamus in the brain (5). The effects of amylin are exerted in concert with those of insulin and reduce the level of glucose in the blood (3, 5). Circulating amylin levels increase in a number of pathological conditions, including obesity, syndrome X, pancreatic cancer, and renal failure (3). Amylin levels together with insulin are raised initially in type 2 diabetes but fall as the disease progresses to a stage where the pancreatic islets of Langerhans ␤-cells that synthesize amylin no longer function (3).One of the hallmarks of type 2 diabetes, found in 90% of patients, is the formation of extracellular amyloid aggregates composed of amylin (3-5). The amyloid deposits accumulate in the interstitial fluid between islet cells and are usually juxtaposed with the ␤-cell membranes (3). Aggregates of amylin are toxic when added to cultures of ␤-cells, so that the amyloid found in situ may be responsible for ␤-cell death as type 2 diabetes progresses (6, 7). Genetic evidence that amylin is directly involved in pathology includes a familial S20G mutation that leads to early ...

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Membrane interaction of islet amyloid polypeptide

Cited by 166 publications

References 86 publications

Islet amyloid polypeptide toxicity and membrane interactions

Islet amyloid polypeptide toxicity and membrane interactions

Calcium-activated Calpain-2 Is a Mediator of Beta Cell Dysfunction and Apoptosis in Type 2 Diabetes

Dynamic α-Helix Structure of Micelle-bound Human Amylin

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