title: Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity.
abstract: Amyloid fiber formation is correlated with pathology in many diseases, including Alzheimer's, Parkinson's, and type II diabetes. Although β-sheet-rich fibrillar protein deposits define this class of disorder, increasing evidence points toward small oligomeric species as being responsible for cell dysfunction and death. The molecular mechanism by which this occurs is unknown, but likely involves the interaction of these species with biological membranes, with a subsequent loss of integrity. Here, we investigate islet amyloid polypeptide, which is implicated in the loss of insulin-secreting cells in type II diabetics. We report the discovery of oligomeric species that arise through stochastic nucleation on membranes and result in disruption of the lipid bilayer. These species are stable, result in all-or-none leakage, and represent a definable protein/lipid phase that equilibrates over time. We characterize the reaction pathway of assembly through the use of an experimental design that includes both ensemble and single-particle evaluations. Complexity in the reaction pathway could not be satisfied using a two-state description of membrane-bound monomer and oligomeric species. We therefore put forward a three-state kinetic framework, one of which we conjecture represents a non-amyloid, non-β-sheet intermediate previously shown to be a candidate therapeutic target.
authors: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
authors: Nicholas B
authors: NB
authors: Last
authors: Elizabeth
authors: E
authors: Rhoades
authors: Andrew D
authors: AD
authors: Miranker
references: J Mol Biol. 2004 Sep 17;342(3):877-87
references: 15342243
references: J Biol Chem. 2008 Jun 20;283(25):17205-10
references: 18442979
references: Biophys J. 2007 Jul 1;93(1):154-63
references: 17434946
references: Methods Enzymol. 2010;472:89-117
references: 20580961
references: J Phys Chem B. 2010 Sep 23;114(37):12018-26
references: 20799752
references: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16863-8
references: 20826442
references: Biochemistry. 2006 Aug 8;45(31):9496-508
references: 16878984
references: Chem Biol. 2009 Sep 25;16(9):943-50
references: 19778722
references: Biochemistry. 2008 Dec 2;47(48):12689-97
references: 18989932
references: Endocr Rev. 2008 May;29(3):303-16
references: 18314421
references: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10427-32
references: 16020533
references: Biophys J. 2001 Aug;81(2):949-59
references: 11463637
references: J Clin Endocrinol Metab. 2004 Aug;89(8):3629-43
references: 15292279
references: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references: 17245412
references: Biophys J. 2010 Nov 3;99(9):2917-25
references: 21044589
references: Biophys J. 2008 Apr 1;94(7):L45-7
references: 18223003
references: J Mol Biol. 1998 Apr 17;277(5):1091-110
references: 9571025
references: Biochemistry. 2010 Apr 13;49(14):3031-9
references: 20201586
references: J Am Chem Soc. 2008 May 21;130(20):6424-9
references: 18444645
references: Biochemistry. 2004 Mar 30;43(12):3590-9
references: 15035629
references: Biophys J. 2008 Mar 1;94(5):1549-50
references: 18065456
references: Neurobiol Aging. 2006 Apr;27(4):570-5
references: 16481071
references: Diabetologia. 2010 Jun;53(6):1046-56
references: 20182863
references: Nat Rev Microbiol. 2005 Mar;3(3):238-50
references: 15703760
references: Annu Rev Biophys. 2009;38:125-52
references: 19416063
references: J Mol Biol. 2004 Aug 27;341(5):1175-87
references: 15321714
references: Annu Rev Biochem. 2006;75:333-66
references: 16756495
references: ILAR J. 2006;47(3):225-33
references: 16804197
references: J Mol Biol. 2009 Oct 23;393(2):383-96
references: 19647750
references: Protein Sci. 2007 Nov;16(11):2334-44
references: 17962399
references: J Biol Chem. 1996 Jan 26;271(4):1988-92
references: 8567648
references: Biophys J. 2008 Mar 1;94(5):1667-80
references: 17921201
references: Trends Biochem Sci. 2008 Feb;33(2):91-100
references: 18182298
references: ACS Chem Biol. 2010 Oct 15;5(10):905-17
references: 20698568