Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes
Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by inv...
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| Veröffentlicht in: | Journal of the American Chemical Society 2017-01, Vol.139 (1), p.137-148 |
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| creator | Martel, Anne Antony, Lucas Gerelli, Yuri Porcar, Lionel Fluitt, Aaron Hoffmann, Kyle Kiesel, Irena Vivaudou, Michel Fragneto, Giovanna de Pablo, Juan J |
| description | Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a “detergent-like” mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies. |
| doi_str_mv | 10.1021/jacs.6b06985 |
| format | Article |
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We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a “detergent-like” mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies.</description><identifier>ISSN: 0002-7863</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/jacs.6b06985</identifier><identifier>PMID: 27997176</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amyloid - chemistry ; Amyloid - genetics ; Amyloid - metabolism ; Animals ; Biochemistry, Molecular Biology ; Cell Membrane - chemistry ; Cell Membrane - genetics ; Cell Membrane - metabolism ; Cell Membrane Permeability - genetics ; Humans ; Islet Amyloid Polypeptide - chemistry ; Islet Amyloid Polypeptide - genetics ; Islet Amyloid Polypeptide - metabolism ; Life Sciences ; Molecular Dynamics Simulation ; Rats ; Structural Biology</subject><ispartof>Journal of the American Chemical Society, 2017-01, Vol.139 (1), p.137-148</ispartof><rights>Copyright © 2016 American Chemical Society</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a358t-241c13ee0ea5c78c79776db670abc26fa321ccf3baa01dcb4544e6a4a092052c3</citedby><cites>FETCH-LOGICAL-a358t-241c13ee0ea5c78c79776db670abc26fa321ccf3baa01dcb4544e6a4a092052c3</cites><orcidid>0000-0002-1232-8519 ; 0000-0001-5655-8298 ; 0000-0002-3526-516X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jacs.6b06985$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jacs.6b06985$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27997176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.univ-grenoble-alpes.fr/hal-01461462$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Martel, Anne</creatorcontrib><creatorcontrib>Antony, Lucas</creatorcontrib><creatorcontrib>Gerelli, Yuri</creatorcontrib><creatorcontrib>Porcar, Lionel</creatorcontrib><creatorcontrib>Fluitt, Aaron</creatorcontrib><creatorcontrib>Hoffmann, Kyle</creatorcontrib><creatorcontrib>Kiesel, Irena</creatorcontrib><creatorcontrib>Vivaudou, Michel</creatorcontrib><creatorcontrib>Fragneto, Giovanna</creatorcontrib><creatorcontrib>de Pablo, Juan J</creatorcontrib><title>Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a “detergent-like” mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies.</description><subject>Amyloid - chemistry</subject><subject>Amyloid - genetics</subject><subject>Amyloid - metabolism</subject><subject>Animals</subject><subject>Biochemistry, Molecular Biology</subject><subject>Cell Membrane - chemistry</subject><subject>Cell Membrane - genetics</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Membrane Permeability - genetics</subject><subject>Humans</subject><subject>Islet Amyloid Polypeptide - chemistry</subject><subject>Islet Amyloid Polypeptide - genetics</subject><subject>Islet Amyloid Polypeptide - metabolism</subject><subject>Life Sciences</subject><subject>Molecular Dynamics Simulation</subject><subject>Rats</subject><subject>Structural Biology</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc9P2zAUxy00BOXHjfPk45AI2E5iJ7tVCEalViABZ8txXlZXTtzZDihH_vOla8suSJYsW5_3ec_-InRByTUljN6slA7XvCK8LPIDNKE5I0lOGf-GJoQQloiCp8foJITVeMxYQY_QMRNlKajgE_SxgLbyqgP8BL4FFY3r8Bv40Ac8bQfrTO1-Q2e0icNPPMWL3kYTQS8786cH_Bz7esCuwbNgIe4r8JOzwxrW0dSAZ10Er_Q_8buJS7xwNVi87xvO0GGjbIDz3X6KXu_vXm4fkvnjr9ntdJ6oNC9iwjKqaQpAQOVaFFqUQvC64oKoSjPeqJRRrZu0UorQWldZnmXAVaZIyUjOdHqKLrfepbJy7U2r_CCdMvJhOpebO0IzPi72Rkf2x5Zdezc-M0TZmqDB2nFg1wdJi5ymJBWsHNGrLaq9C8FD8-mmRG4CkpuA5C6gEf--M_dVC_UnvE_kf-tN1cr1vhs_5WvXX2xfmzU</recordid><startdate>20170111</startdate><enddate>20170111</enddate><creator>Martel, Anne</creator><creator>Antony, Lucas</creator><creator>Gerelli, Yuri</creator><creator>Porcar, Lionel</creator><creator>Fluitt, Aaron</creator><creator>Hoffmann, Kyle</creator><creator>Kiesel, Irena</creator><creator>Vivaudou, Michel</creator><creator>Fragneto, Giovanna</creator><creator>de Pablo, Juan J</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-1232-8519</orcidid><orcidid>https://orcid.org/0000-0001-5655-8298</orcidid><orcidid>https://orcid.org/0000-0002-3526-516X</orcidid></search><sort><creationdate>20170111</creationdate><title>Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes</title><author>Martel, Anne ; Antony, Lucas ; Gerelli, Yuri ; Porcar, Lionel ; Fluitt, Aaron ; Hoffmann, Kyle ; Kiesel, Irena ; Vivaudou, Michel ; Fragneto, Giovanna ; de Pablo, Juan J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a358t-241c13ee0ea5c78c79776db670abc26fa321ccf3baa01dcb4544e6a4a092052c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amyloid - chemistry</topic><topic>Amyloid - genetics</topic><topic>Amyloid - metabolism</topic><topic>Animals</topic><topic>Biochemistry, Molecular Biology</topic><topic>Cell Membrane - chemistry</topic><topic>Cell Membrane - genetics</topic><topic>Cell Membrane - metabolism</topic><topic>Cell Membrane Permeability - genetics</topic><topic>Humans</topic><topic>Islet Amyloid Polypeptide - chemistry</topic><topic>Islet Amyloid Polypeptide - genetics</topic><topic>Islet Amyloid Polypeptide - metabolism</topic><topic>Life Sciences</topic><topic>Molecular Dynamics Simulation</topic><topic>Rats</topic><topic>Structural Biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martel, Anne</creatorcontrib><creatorcontrib>Antony, Lucas</creatorcontrib><creatorcontrib>Gerelli, Yuri</creatorcontrib><creatorcontrib>Porcar, Lionel</creatorcontrib><creatorcontrib>Fluitt, Aaron</creatorcontrib><creatorcontrib>Hoffmann, Kyle</creatorcontrib><creatorcontrib>Kiesel, Irena</creatorcontrib><creatorcontrib>Vivaudou, Michel</creatorcontrib><creatorcontrib>Fragneto, Giovanna</creatorcontrib><creatorcontrib>de Pablo, Juan J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of the American Chemical Society</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martel, Anne</au><au>Antony, Lucas</au><au>Gerelli, Yuri</au><au>Porcar, Lionel</au><au>Fluitt, Aaron</au><au>Hoffmann, Kyle</au><au>Kiesel, Irena</au><au>Vivaudou, Michel</au><au>Fragneto, Giovanna</au><au>de Pablo, Juan J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes</atitle><jtitle>Journal of the American Chemical Society</jtitle><addtitle>J. Am. Chem. Soc</addtitle><date>2017-01-11</date><risdate>2017</risdate><volume>139</volume><issue>1</issue><spage>137</spage><epage>148</epage><pages>137-148</pages><issn>0002-7863</issn><eissn>1520-5126</eissn><abstract>Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a “detergent-like” mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27997176</pmid><doi>10.1021/jacs.6b06985</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-1232-8519</orcidid><orcidid>https://orcid.org/0000-0001-5655-8298</orcidid><orcidid>https://orcid.org/0000-0002-3526-516X</orcidid></addata></record> |
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| subjects | Amyloid - chemistry Amyloid - genetics Amyloid - metabolism Animals Biochemistry, Molecular Biology Cell Membrane - chemistry Cell Membrane - genetics Cell Membrane - metabolism Cell Membrane Permeability - genetics Humans Islet Amyloid Polypeptide - chemistry Islet Amyloid Polypeptide - genetics Islet Amyloid Polypeptide - metabolism Life Sciences Molecular Dynamics Simulation Rats Structural Biology |
| title | Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes |
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