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Article ; Online: Targeting hIAPP fibrillation: A new paradigm to prevent β-cell death?

Guillemain, Ghislaine / Lacapere, Jean-Jacques / Khemtemourian, Lucie

Biochimica et biophysica acta. Biomembranes

2022 Volume 1864, Issue 10, Page(s) 184002

Abstract: Loss of pancreatic β-cell mass is deleterious for type 2 diabetes patients since it reduces insulin production, critical for glucose homeostasis. The main research axis developed over the last few years was to generate new pancreatic β-cells or to ... ...

Abstract	Loss of pancreatic β-cell mass is deleterious for type 2 diabetes patients since it reduces insulin production, critical for glucose homeostasis. The main research axis developed over the last few years was to generate new pancreatic β-cells or to transplant pancreatic islets as occurring for some specific type 1 diabetes patients. We evaluate here a new paradigm consisting in preservation of β-cells by prevention of human islet amyloid polypeptide (hIAPP) oligomers and fibrils formation leading to pancreatic β-cell death. We review the hIAPP physiology and the pathology that contributes to β-cell destruction, deciphering the various cellular steps that could be involved. Recent progress in understanding other amyloidosis such as Aβ, Tau, α-synuclein or prion, involved in neurodegenerative processes linked with inflammation, has opened new research lines of investigations to preserve neuronal cells. We evaluate and estimate their transposition to the pancreatic β-cells preservation. Among them is the control of reactive oxygen species (ROS) production occurring with inflammation and the possible implication of the mitochondrial translocator protein as a diagnostic and therapeutic target. The present review also focuses on other amyloid forming proteins from molecular to physiological and physiopathological points of view that could help to better decipher hIAPP-induced β-cell death mechanisms and to prevent hIAPP fibril formation.
MeSH term(s)	Amyloid/chemistry ; Cell Death ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Inflammation ; Islet Amyloid Polypeptide/chemistry
Chemical Substances	Amyloid ; Islet Amyloid Polypeptide
Language	English
Publishing date	2022-07-19
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2642 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2642 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamem.2022.184002
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Article ; Online: Fibril elongation by human islet amyloid polypeptide is the main event linking aggregation to membrane damage.

Elenbaas, Barend O W / Kremsreiter, Stefanie M / Khemtemourian, Lucie / Killian, J Antoinette / Sinnige, Tessa

BBA advances

2023 Volume 3, Page(s) 100083

Abstract: The aggregation of human islet amyloid polypeptide (hIAPP) is linked to the death of pancreatic β-cells in type II diabetes. The process of fibril formation by hIAPP is thought to cause membrane damage, but the precise mechanisms are still unclear. ... ...

Abstract	The aggregation of human islet amyloid polypeptide (hIAPP) is linked to the death of pancreatic β-cells in type II diabetes. The process of fibril formation by hIAPP is thought to cause membrane damage, but the precise mechanisms are still unclear. Previously, we showed that the aggregation of hIAPP in the presence of membranes containing anionic lipids is dominated by secondary nucleation events, which occur at the interface between existing fibrils and the membrane surface. Here, we used vesicles with different lipid composition to explore the connection between hIAPP aggregation and vesicle leakage. We found that different anionic lipids promote hIAPP aggregation to the same extent, whereas remarkably stochastic behaviour is observed on purely zwitterionic membranes. Vesicle leakage induced by hIAPP consists of two distinct phases for any of the used membrane compositions: (i) an initial phase in which hIAPP binding causes a certain level of leakage that is strongly dependent on osmotic conditions, membrane composition and the used dye, and (ii) a main leakage event that we attribute to elongation of hIAPP fibrils, based on seeded experiments. Altogether, our results shed more light on the relationship between hIAPP fibril formation and membrane damage, and strongly suggest that oligomeric intermediates do not considerably contribute to vesicle leakage.
Language	English
Publishing date	2023-02-14
Publishing country	Netherlands
Document type	Journal Article
ISSN	2667-1603
ISSN (online)	2667-1603
DOI	10.1016/j.bbadva.2023.100083
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Article ; Online: Membrane-Catalyzed Aggregation of Islet Amyloid Polypeptide Is Dominated by Secondary Nucleation.

Elenbaas, Barend O W / Khemtemourian, Lucie / Killian, J Antoinette / Sinnige, Tessa

Biochemistry

2022 Volume 61, Issue 14, Page(s) 1465–1472

Abstract: Type II diabetes is characterized by the loss of pancreatic β-cells. This loss is thought to be a consequence of membrane disruption, caused by the aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils. However, the molecular mechanisms of ...

Abstract	Type II diabetes is characterized by the loss of pancreatic β-cells. This loss is thought to be a consequence of membrane disruption, caused by the aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils. However, the molecular mechanisms of IAPP aggregation in the presence of membranes have remained unclear. Here, we use kinetic analysis to elucidate the aggregation mechanism of IAPP in the presence of mixed zwitterionic and anionic lipid membranes. The results converge to a model in which aggregation on the membrane is strongly dominated by secondary nucleation, that is, the formation of new nuclei on the surface of existing fibrils. The critical nucleus consists of a single IAPP molecule, and anionic lipids catalyze both primary and secondary nucleation, but not elongation. The fact that anionic lipids promote secondary nucleation implies that these events take place at the interface between the membrane and existing fibrils, demonstrating that fibril growth occurs at least to some extent on the membrane surface. These new insights into the mechanism of IAPP aggregation on membranes may help to understand IAPP toxicity and will be important for the development of therapeutics to prevent β-cell death in type II diabetes.
MeSH term(s)	Amyloid/chemistry ; Catalysis ; Diabetes Mellitus, Type 2 ; Humans ; Islet Amyloid Polypeptide/chemistry ; Kinetics ; Lipids
Chemical Substances	Amyloid ; Islet Amyloid Polypeptide ; Lipids
Language	English
Publishing date	2022-06-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.2c00184
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Article: Structural Dissection of the First Events Following Membrane Binding of the Islet Amyloid Polypeptide.

Khemtemourian, Lucie / Fatafta, Hebah / Davion, Benoit / Lecomte, Sophie / Castano, Sabine / Strodel, Birgit

Frontiers in molecular biosciences

2022 Volume 9, Page(s) 849979

Abstract: The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of ... ...

Abstract	The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of IAPP aggregation and being the target of IAPP toxicity. Using ATR-FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Distinct IAPP-membrane interaction modes for the various IAPP variants are revealed. Membrane binding causes IAPP to fold into an amphipathic
Language	English
Publishing date	2022-03-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2022.849979
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Article ; Online: Anionic lipids induce a fold-unfold transition in the membrane-translocating Engrailed homeodomain.

Carlier, Ludovic / Samson, Damien / Khemtemourian, Lucie / Joliot, Alain / Fuchs, Patrick F J / Lequin, Olivier

Biochimica et biophysica acta. Biomembranes

2022 Volume 1864, Issue 11, Page(s) 184030

Abstract: Homeoprotein transcription factors have the property of interacting with membranes through their DNA-binding homeodomain, which is involved in unconventional internalization and secretion. Both processes depend on membrane-translocating events but their ... ...

Abstract	Homeoprotein transcription factors have the property of interacting with membranes through their DNA-binding homeodomain, which is involved in unconventional internalization and secretion. Both processes depend on membrane-translocating events but their detailed molecular mechanisms are still poorly understood. We have previously characterized the conformational properties of Engrailed 2 homeodomain (EnHD) in aqueous solution and in micelles as membrane-mimetic environments. In the present study, we used small isotropic lipid bicelles as a more relevant membrane-mimetic model to characterize the membrane-bound state of EnHD. We show that lipid bicelles, in contrast to micelles, adequately reproduce the requirement of anionic lipids in the membrane binding and conformational transition of EnHD. The fold-unfold transition of EnHD induced by anionic lipids was characterized by NMR using
MeSH term(s)	Homeodomain Proteins/chemistry ; Lipids ; Micelles ; Molecular Dynamics Simulation ; Protein Structure, Secondary
Chemical Substances	Homeodomain Proteins ; Lipids ; Micelles
Language	English
Publishing date	2022-08-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2642 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2642 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamem.2022.184030
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Article: Investigation of the effects of two major secretory granules components, insulin and zinc, on human-IAPP amyloid aggregation and membrane damage

Khemtemourian, Lucie / Antoniciello, Federico / Sahoo, Bikash R / Decossas, Marion / Lecomte, Sophie / Ramamoorthy, Ayyalusamy

Elsevier B.V. Chemistry and physics of lipids. 2021 July, v. 237

2021

Abstract: Human islet amyloid polypeptide (hIAPP) is a highly amyloidogenic peptide found in pancreatic islets of type-2 diabetes (T2D) patients. Under certain conditions, hIAPP is able to form amyloid fibrils that play a role in the progression of T2D. hIAPP is ... ...

Abstract	Human islet amyloid polypeptide (hIAPP) is a highly amyloidogenic peptide found in pancreatic islets of type-2 diabetes (T2D) patients. Under certain conditions, hIAPP is able to form amyloid fibrils that play a role in the progression of T2D. hIAPP is synthesized in the β-cell of the pancreas and stored in the secretory granules before being released into the extracellular compartment. It has been suggested that natural stabilizing agents, such as insulin or zinc present in the secretory granules with hIAPP could prevent hIAPP fibril formation. The difference in the amino acid sequences of IAPP among species strongly correlates with amyloidogenicity and toxicity. The residue histidine at position 18 is known to be important in modulating the fibril formation, membrane leakage and toxicity. In this study, we have synthesized four analogues of hIAPP (H18R-IAPP, H18K-IAPP, H18A-IAPP and H18E-IAPP) and characterized their aggregation with either insulin or zinc in order to determine the effect of the residue-18 on the insulin-IAPP and zinc-IAPP interactions using a variety of biophysical experiments including thioflavin-T fluorescence, transmission electron microscopy imaging, circular dichroism, and NMR spectroscopy. We show that insulin reduced hIAPP fibril formation both in solution and in the presence of membrane and hIAPP-membrane damage and that the interactions are somewhat mediated by the residue-18. In addition, our results reveal that zinc affects the process of hIAPP fibril formation in solution but not in the presence of membrane. Our results indicate that the nature of the residue-18 is important for zinc binding. Based on this observation, we hypothesize that zinc binds to the residues in the N-terminal region of hIAPP, which is not accessible in the presence of membrane due to its strong interaction with lipids.
Keywords	amyloid ; circular dichroism spectroscopy ; fluorescence ; histidine ; humans ; insulin ; noninsulin-dependent diabetes mellitus ; nuclear magnetic resonance spectroscopy ; polypeptides ; toxicity ; transmission electron microscopy ; zinc
Language	English
Dates of publication	2021-07
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2021.105083
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Structural Dissection of the First Events Following Membrane Binding of the Islet Amyloid Polypeptide

Lucie Khemtemourian / Hebah Fatafta / Benoit Davion / Sophie Lecomte / Sabine Castano / Birgit Strodel

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Abstract	The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of IAPP aggregation and being the target of IAPP toxicity. Using ATR-FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Distinct IAPP-membrane interaction modes for the various IAPP variants are revealed. Membrane binding causes IAPP to fold into an amphipathic α-helix, which in the case of H18K-, and H18R-IAPP readily moves beyond the headgroup region. For all IAPP variants but H18E-IAPP, the membrane-bound helix is an intermediate on the way to amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel β-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel β-sheets as well as amorphous aggregates. Our results emphasize the decisive role of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good therapeutic target for destabilizing membrane-bound IAPP fibrils to inhibit their toxic actions.
Keywords	islet amyloid polypeptide ; type 2 diabetes mellitus ; amylin ; amyloid aggregation ; peptide-membrane interactions ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Investigation of the effects of two major secretory granules components, insulin and zinc, on human-IAPP amyloid aggregation and membrane damage.

Khemtemourian, Lucie / Antoniciello, Federico / Sahoo, Bikash R / Decossas, Marion / Lecomte, Sophie / Ramamoorthy, Ayyalusamy

Chemistry and physics of lipids

2021 Volume 237, Page(s) 105083

Abstract	Human islet amyloid polypeptide (hIAPP) is a highly amyloidogenic peptide found in pancreatic islets of type-2 diabetes (T2D) patients. Under certain conditions, hIAPP is able to form amyloid fibrils that play a role in the progression of T2D. hIAPP is synthesized in the β-cell of the pancreas and stored in the secretory granules before being released into the extracellular compartment. It has been suggested that natural stabilizing agents, such as insulin or zinc present in the secretory granules with hIAPP could prevent hIAPP fibril formation. The difference in the amino acid sequences of IAPP among species strongly correlates with amyloidogenicity and toxicity. The residue histidine at position 18 is known to be important in modulating the fibril formation, membrane leakage and toxicity. In this study, we have synthesized four analogues of hIAPP (H18R-IAPP, H18K-IAPP, H18A-IAPP and H18E-IAPP) and characterized their aggregation with either insulin or zinc in order to determine the effect of the residue-18 on the insulin-IAPP and zinc-IAPP interactions using a variety of biophysical experiments including thioflavin-T fluorescence, transmission electron microscopy imaging, circular dichroism, and NMR spectroscopy. We show that insulin reduced hIAPP fibril formation both in solution and in the presence of membrane and hIAPP-membrane damage and that the interactions are somewhat mediated by the residue-18. In addition, our results reveal that zinc affects the process of hIAPP fibril formation in solution but not in the presence of membrane. Our results indicate that the nature of the residue-18 is important for zinc binding. Based on this observation, we hypothesize that zinc binds to the residues in the N-terminal region of hIAPP, which is not accessible in the presence of membrane due to its strong interaction with lipids.
MeSH term(s)	Amino Acid Sequence ; Humans ; Insulin/metabolism ; Islet Amyloid Polypeptide/chemistry ; Islet Amyloid Polypeptide/metabolism ; Microscopy, Electron, Transmission ; Protein Aggregates/physiology ; Protein Binding ; Spectrometry, Fluorescence ; Unilamellar Liposomes/chemistry ; Unilamellar Liposomes/metabolism ; Zinc/metabolism
Chemical Substances	Insulin ; Islet Amyloid Polypeptide ; Protein Aggregates ; Unilamellar Liposomes ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2021-04-19
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2021.105083
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Article: Membrane-Catalyzed Aggregation of Islet Amyloid Polypeptide Is Dominated by Secondary Nucleation

Elenbaas, Barend O. W. / Khemtemourian, Lucie / Killian, J. Antoinette / Sinnige, Tessa

Biochemistry. 2022 June 24, v. 61, no. 14

2022

Abstract	Type II diabetes is characterized by the loss of pancreatic β-cells. This loss is thought to be a consequence of membrane disruption, caused by the aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils. However, the molecular mechanisms of IAPP aggregation in the presence of membranes have remained unclear. Here, we use kinetic analysis to elucidate the aggregation mechanism of IAPP in the presence of mixed zwitterionic and anionic lipid membranes. The results converge to a model in which aggregation on the membrane is strongly dominated by secondary nucleation, that is, the formation of new nuclei on the surface of existing fibrils. The critical nucleus consists of a single IAPP molecule, and anionic lipids catalyze both primary and secondary nucleation, but not elongation. The fact that anionic lipids promote secondary nucleation implies that these events take place at the interface between the membrane and existing fibrils, demonstrating that fibril growth occurs at least to some extent on the membrane surface. These new insights into the mechanism of IAPP aggregation on membranes may help to understand IAPP toxicity and will be important for the development of therapeutics to prevent β-cell death in type II diabetes.
Keywords	amyloid ; death ; kinetics ; lipids ; models ; polypeptides ; therapeutics ; toxicity ; zwitterions
Language	English
Dates of publication	2022-0624
Size	p. 1465-1472.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.2c00184
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Article ; Online: Identification of a human estrogen receptor α tetrapeptidic fragment with dual antiproliferative and anti-nociceptive action.

Jouffre, Baptiste / Acramel, Alexandre / Belnou, Mathilde / Santolla, Maria Francesca / Talia, Marianna / Lappano, Rosamaria / Nemati, Fariba / Decaudin, Didier / Khemtemourian, Lucie / Liu, Wang-Qing / Maggiolini, Marcello / Eschalier, Alain / Mallet, Christophe / Jacquot, Yves

Scientific reports

2023 Volume 13, Issue 1, Page(s) 1326

Abstract: The synthetic peptide ERα17p (sequence: PLMIKRSKKNSLALSLT), which corresponds to the 295-311 region of the human estrogen receptor α (ERα), induces apoptosis in breast cancer cells. In mice and at low doses, it promotes not only the decrease of the size ... ...

Abstract	The synthetic peptide ERα17p (sequence: PLMIKRSKKNSLALSLT), which corresponds to the 295-311 region of the human estrogen receptor α (ERα), induces apoptosis in breast cancer cells. In mice and at low doses, it promotes not only the decrease of the size of xenografted triple-negative human breast tumors, but also anti-inflammatory and anti-nociceptive effects. Recently, we have shown that these effects were due to its interaction with the seven-transmembrane G protein-coupled estrogen receptor GPER. Following modeling studies, the C-terminus of this peptide (sequence: NSLALSLT) remains compacted at the entrance of the GPER ligand-binding pocket, whereas its N-terminus (sequence: PLMI) engulfs in the depth of the same pocket. Thus, we have hypothesized that the PLMI motif could support the pharmacological actions of ERα17p. Here, we show that the PLMI peptide is, indeed, responsible for the GPER-dependent antiproliferative and anti-nociceptive effects of ERα17p. By using different biophysical approaches, we demonstrate that the NSLALSLT part of ERα17p is responsible for aggregation. Overall, the tetrapeptide PLMI, which supports the action of the parent peptide ERα17p, should be considered as a hit for the synthesis of new GPER modulators with dual antiproliferative and anti-nociceptive actions. This study highlights also the interest to modulate GPER for the control of pain.
MeSH term(s)	Animals ; Humans ; Mice ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Estrogens ; Peptides ; Receptors, G-Protein-Coupled ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	Estrogen Receptor alpha ; Estrogens ; Peptides ; Receptors, G-Protein-Coupled ; GPER1 protein, human ; estrogen receptor alpha (295-311), human
Language	English
Publishing date	2023-01-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-28062-9
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