title: Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition.
abstract: Amyloid formation by islet amyloid polypeptide (IAPP) contributes to β-cell dysfunction in type 2 diabetes. Perturbation of the β-cell membrane may contribute to IAPP-induced toxicity. We examine the effects of lipid composition, salt, and buffer on IAPP amyloid formation and on the ability of IAPP to induce leakage of model membranes. Even low levels of anionic lipids promote amyloid formation and membrane permeabilization. Increasing the percentage of the anionic lipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) or 1,2-dioleoyl-sn-glycero-3-phospho(1'-rac-glycerol), enhances the rate of amyloid formation and increases the level of membrane permeabilization. The choice of zwitterionic lipid has no noticeable effect on membrane-catalyzed amyloid formation but in most cases affects leakage, which tends to decrease in the following order: 1,2-dioleoyl-sn-glycero-3-phosphocholine > 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine > sphingomyelin. Uncharged lipids that increase the level of membrane order weaken the ability of IAPP to induce leakage. Leakage is due predominately to pore formation rather than complete disruption of the vesicles under the conditions used in these studies. Cholesterol at or below physiological levels significantly reduces the rate of vesicle-catalyzed IAPP amyloid formation and decreases the susceptibility to IAPP-induced leakage. The effects of cholesterol on amyloid formation are masked by 25 mol % POPS. Overall, there is a strong inverse correlation between the time to form amyloid and the extent of vesicle leakage. NaCl reduces the rate of membrane-catalyzed amyloid formation by anionic vesicles, but accelerates amyloid formation in solution. The implications for IAPP membrane interactions are discussed, as is the possibility that the loss of phosphatidylserine asymmetry enhances IAPP amyloid formation and membrane damage in vivo via a positive feedback loop.
authors.affiliation: Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States.
authors.forename: Johnna R
authors.initials: JR
authors.lastname: St Clair
authors.affiliation: Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.|Department of Biochemistry and Cell Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States.
authors.forename: Erwin
authors.initials: E
authors.lastname: London
authors.affiliation: Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.|Graduate Program in Biochemistry and Structural Biology, Stony Brook University , Stony Brook, New York 11794-5215, United States.
authors.forename: Daniel P
authors.identifier: http://orcid.org/0000-0003-3248-7493
authors.initials: DP
authors.lastname: Raleigh
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D005997:Glycerylphosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000737:chemistry; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry / Q000378:metabolism; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D010718:Phosphatidylserines; D013109:Sphingomyelins; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; D012965:Sodium Chloride; D005997:Glycerylphosphorylcholine; C051388:1,2-dioleoyl-sn-glycero-3-phosphoglycerol; D002784:Cholesterol; C017251:1,2-oleoylphosphatidylcholine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine