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In type II diabetes, IAPP aggregates in a process that is associated with \u03b2\u2010cell dysfunction and loss of \u03b2\u2010cell mass. The relationship between IAPP's conformational landscape and its capacity to mediate cell death remains poorly understood. We have addressed these unknowns by comparing the cytotoxic effects of sequence variants with differing \u03b1\u2010helical and amyloid propensities. IAPP was previously shown to oligomerize cooperatively on binding to lipid bilayers. Here, comparable transitions are evident in cell culture and are associated with a change in subcellular localization to the mitochondria under toxic conditions. Notably, we find that this toxic gain of function maps to IAPP's capacity to adopt aggregated membrane\u2010bound \u03b1\u2010helical, and not \u03b2\u2010sheet, states. Our findings suggest that upon \u03b1\u2010helical mediated oligomerization, IAPP acquires cell\u2010penetrating peptide (CPP) properties, facilitating access to the mitochondrial compartment, resulting in its dysfunction.\u2014Magzoub, M. Miranker, A. D. Concentration\u2010dependent transitions govern the subcellular localization of islet amyloid polypeptide.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    26, 1228\u20101238 (2012).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.11-194613","type":"journal-article","created":{"date-parts":[[2011,12,19]],"date-time":"2011-12-19T21:56:51Z","timestamp":1324331811000},"page":"1228-1238","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Concentration\u2010dependent transitions govern the subcellular localization of islet amyloid polypeptide"],"prefix":"10.1096","volume":"26","author":[{"given":"Mazin","family":"Magzoub","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry Yale University New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Miranker","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry Yale University New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,12,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0037"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200008103430607"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.2.241"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1304-4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0405"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0282(2001)60:6<438::AID-BIP10182>3.0.CO;2-A"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.13.5036"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.2337\/db05-1672"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909024107"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703306104"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.050708.133622"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.145"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201102887"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.07.077"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.062486907"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809085200"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801383200"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja9010095"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2009.08.013"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(97)01168-5"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.9.2304"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.6.1509"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00082.2006"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.3.491"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102356108"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(83)90303-4"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.98.4.1556"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-679X(08)60193-4"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.139.1.63"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.5.873"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2010.07.056"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi701427q"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.3.424"},{"key":"e_1_2_7_35_1","first-page":"609","article-title":"Human islet amyloid polypeptide expression in COS\u20101 cells. 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