Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin

Peptide mediated gain-of-toxic function is central to pathology in Alzheimer’s, Parkinson’s and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here we focus on islet amyloid polypeptide (IAPP) mediated loss-of-insulin secreting cells in patients with diabetes. Newly developed methods enable structure-function enquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two classes of poration occur; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilising non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalisable approach for enquiry applicable to other partially ordered protein assemblies.

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“…ADM-116 is a recently developed 16 , 17 small molecule inhibitor of IAPP-induced cellular toxicity (Supplementary Fig. 7 ) ( P = 0.0001).…”

Section: Resultsmentioning

confidence: 99%

“…In summary, this ligand shows no effect on small sieve-size leakage processes and wholly inhibits formation of large sieve states. As ADM-116 binding to IAPP is sequence and conformation specific 16 , 17 , this suggests that structurally distinct assemblies mediate the two forms of observed leakage.…”

Section: Resultsmentioning

confidence: 99%

Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

et al. 2018

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“…Recently, we reported the development of a small molecule, ADM-116, which binds and stabilizes a-helical, membrane bound conformations of IAPP (Kumar et al, 2016a;Kumar et al, 2016b).…”

Section: Resultsmentioning

confidence: 99%

“…Recently we reported the development of a tetraquinoline amide, ADM-116. This molecule demonstrates cytotoxic rescue through specific binding interactions with a-helical states of membrane bound IAPP (Kumar et al, 2016a;Kumar et al, 2016b). Moreover, ADM-116 can cross plasma membranes and act on intracellular IAPP making it ideally suited for making matched assessments inside cells (see below).…”

Section: Resultsmentioning

confidence: 99%

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Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration

Birol

Kumar

Rhoades

et al. 2016

Preprint

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Peptide mediated gain-of-toxic function is central to pathology in Alzheimer's, Parkinson's and diabetes.In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here, we focus on islet amyloid polypeptide (IAPP) mediated loss of insulin secreting cells in diabetics. Newly developed methods enable structure-function inquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two class of pores coexist; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilizing non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalizable approach for inquiry applicable to other partially ordered protein assemblies. Highlights• The peptide amyloid precursor, IAPP, forms two classes of membrane porating oligomers.• The two classes have a >100-fold difference in pore size with the large pore form correlated with mitochondrial depolarization and toxicity.• A drug-like molecule distinguishes between the two oligomer classes and rescues toxicity by stabilizing non-toxic poration without displacing IAPP from the mitochondria.• The mechanism of pore-forming oligomer assembly includes stepwise coalescence of smaller, dynamic assemblies.

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Multivalent Interactions between an Aromatic Helical Foldamer and a DNA G‐Quadruplex in the Solid State

et al. 2016

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Quinoline-based oligoamide foldamers have been identified as a potent class of ligands for G-quadruplex DNA. Their helical structure is thought to target G-quadruplex loops or grooves and not G-tetrads. We report a co-crystal structure of the antiparallel hairpin dimeric DNA G-quadruplex (G T G ) with tetramer 1-a helically folded oligo-quinolinecarboxamide bearing cationic side chains-that is consistent with this hypothesis. Multivalent foldamer-DNA interactions that modify the packing of (G T G ) in the solid state are observed.

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Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin

Cited by 23 publications

References 26 publications

Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration

Multivalent Interactions between an Aromatic Helical Foldamer and a DNA G‐Quadruplex in the Solid State

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