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Article ; Online: A solenoid design for assessing determinants of parallel β-sheet registration.

White, Ellen M / Miranker, Andrew D

Protein engineering, design & selection : PEDS

2015 Volume 28, Issue 12, Page(s) 577–583

Abstract: A novel protein construct is presented that combines a homotrimeric, triple-stranded β-helix as a guest to a homotrimeric foldon unit from bacteriophage T4 fibritin. The β-helical solenoid selected is short (46 residues) and is part of a subdomain of the ...

Abstract	A novel protein construct is presented that combines a homotrimeric, triple-stranded β-helix as a guest to a homotrimeric foldon unit from bacteriophage T4 fibritin. The β-helical solenoid selected is short (46 residues) and is part of a subdomain of the T4 cell-puncturing device. The resultant design is trimeric and displays greatly enhanced stability over each sub-component alone. The intended goal is a design that will enable evaluation of sequence determinants that promote in-register versus out-of-register parallel β-sheet homotrimerization. Towards that end, the importance of a set of three buried salt-bridges was evaluated by converting them to residues otherwise consistently found throughout the natural solenoid at the same positions. The critical role of the charged residues in the salt-bridges was evident in that their elimination resulted in amyloid-like aggregation.
MeSH term(s)	Amino Acid Sequence ; Amyloid/chemistry ; Biochemistry/methods ; Fluorescent Dyes ; Models, Molecular ; Molecular Sequence Data ; Protein Structure, Secondary ; Viral Proteins/ultrastructure
Chemical Substances	Amyloid ; Fluorescent Dyes ; Viral Proteins ; fibritin protein, Enterobacteria phage T4
Language	English
Publishing date	2015-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1466729-0
ISSN	1741-0134 ; 1460-213X ; 1741-0126 ; 0269-2139
ISSN (online)	1741-0134 ; 1460-213X
ISSN	1741-0126 ; 0269-2139
DOI	10.1093/protein/gzv053
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Article ; Online: Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein.

Birol, Melissa / Wojcik, Slawomir P / Miranker, Andrew D / Rhoades, Elizabeth

PLoS biology

2019 Volume 17, Issue 6, Page(s) e3000318

Abstract: Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively ... ...

Abstract	Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively unexplored. Here, we report that αSacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αSun). We identify complex N-linked glycans as binding partners for αSacetyl and demonstrate that cellular internalization of αSacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αSacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αSacetyl. Importantly, our results are specific to αSacetyl because αSun does not demonstrate sensitivity for N-linked glycans in any of our assays. Our study identifies extracellular N-linked glycans-and the glycoprotein neurexin 1β specifically-as key modulators of neuronal uptake of αSacetyl, drawing attention to the potential therapeutic value of αSacetyl-glycan interactions.
MeSH term(s)	Acetylation ; Animals ; Biological Transport ; Cell Line, Tumor ; Glycoproteins/metabolism ; HEK293 Cells ; Humans ; Mice ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/physiology ; Neurons/metabolism ; Parkinson Disease/metabolism ; Polysaccharides/metabolism ; Polysaccharides/physiology ; Primary Cell Culture ; alpha-Synuclein/metabolism
Chemical Substances	Glycoproteins ; Nerve Tissue Proteins ; Polysaccharides ; alpha-Synuclein ; neurexin Ibeta (156532-80-8)
Language	English
Publishing date	2019-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000318
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Article ; Online: Fiber-dependent and -independent toxicity of islet amyloid polypeptide.

Schlamadinger, Diana E / Miranker, Andrew D

Biophysical journal

2014 Volume 107, Issue 11, Page(s) 2559–2566

Abstract: The 37-residue peptide hormone islet amyloid polypeptide (IAPP) plays a central role in diabetes pathology. Although its amyloid fiber aggregation kinetics and cytotoxicity to β-cells are well documented, few reports have directly assessed the role of ... ...

Abstract	The 37-residue peptide hormone islet amyloid polypeptide (IAPP) plays a central role in diabetes pathology. Although its amyloid fiber aggregation kinetics and cytotoxicity to β-cells are well documented, few reports have directly assessed the role of fibers in cell-based toxicity experiments. Here, we report that amyloid formation of IAPP can be strongly inhibited by the extracellular environment of live cells. For example, fiber formation is more strongly suppressed in cell culture medium than in aqueous buffer. The serum component of the medium is responsible for this inhibition. Although amyloid formation was previously shown to be catalyzed by both synthetic and chloroform-extracted phospholipid surfaces, it is instead inhibited by membrane surfaces prepared directly from the plasma membranes of an immortal β-cell line. This disparity is reconciled by direct assessment of fibers in cell-culture-based toxicity experiments. We discovered that fibers are nontoxic if they are washed free of adsorbed nonfibrillar components. Moreover, toxicity is not only rescued when monomers are added back to fibers but is greater than what is observed from the precursor alone. Our results are interpreted in light of the capacity of the fiber surface to template amyloid nucleation.
MeSH term(s)	Amyloid/metabolism ; Animals ; COS Cells ; Cell Line, Tumor ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Chlorocebus aethiops ; Culture Media/pharmacology ; Humans ; Islet Amyloid Polypeptide/toxicity ; Protein Binding/drug effects ; Rats ; Unilamellar Liposomes/metabolism
Chemical Substances	Amyloid ; Culture Media ; Islet Amyloid Polypeptide ; Unilamellar Liposomes
Language	English
Publishing date	2014-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2014.09.047
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 2: Show issues

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Article ; Online: Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid.

Birol, Melissa / Kumar, Sunil / Rhoades, Elizabeth / Miranker, Andrew D

Nature communications

2018 Volume 9, Issue 1, Page(s) 1312

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Amyloid/chemistry ; Amyloidosis/metabolism ; Animals ; Cell Line ; Cell Survival ; Diabetes Mellitus/metabolism ; Fluorescence Resonance Energy Transfer ; Gain of Function Mutation ; Green Fluorescent Proteins/metabolism ; Humans ; Insulin-Secreting Cells/metabolism ; Insulinoma/metabolism ; Islet Amyloid Polypeptide/metabolism ; Microscopy, Confocal ; Mitochondria/metabolism ; Protein Conformation ; Rats
Chemical Substances	Amyloid ; Islet Amyloid Polypeptide ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2018-04-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-018-03651-9
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Article ; Online: A foldamer approach to targeting membrane bound helical states of islet amyloid polypeptide.

Kumar, Sunil / Miranker, Andrew D

Chemical communications (Cambridge, England)

2013 Volume 49, Issue 42, Page(s) 4749–4751

Abstract: A small molecule, protein mimetic based approach is shown to specifically inhibit lipid catalysed self-assembly of islet amyloid polypeptide (IAPP). The lipid-bound oligomerization of this peptide is implicated in cellular dysfunction of insulin ... ...

Abstract	A small molecule, protein mimetic based approach is shown to specifically inhibit lipid catalysed self-assembly of islet amyloid polypeptide (IAPP). The lipid-bound oligomerization of this peptide is implicated in cellular dysfunction of insulin secreting β-cells in type II diabetes.
MeSH term(s)	Carboxylic Acids/chemistry ; Cell Membrane ; Islet Amyloid Polypeptide/chemistry ; Peptidomimetics ; Peptoids/chemistry ; Phosphatidylcholines/chemistry ; Phosphatidylglycerols/chemistry ; Quinolines/chemistry
Chemical Substances	Carboxylic Acids ; Islet Amyloid Polypeptide ; Peptidomimetics ; Peptoids ; Phosphatidylcholines ; Phosphatidylglycerols ; Quinolines ; 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (66322-31-4) ; 1,2-oleoylphosphatidylcholine (EDS2L3ODLV)
Language	English
Publishing date	2013-03-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/c3cc41452c
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Article ; Online: Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin.

Kumar, Sunil / Birol, Melissa / Miranker, Andrew D

Chemical communications (Cambridge, England)

2016 Volume 52, Issue 38, Page(s) 6391–6394

Abstract: An oligoquinoline foldamer library was synthesized and screened for antagonism of lipid bilayer catalysed assembly of islet amyloid polypeptide (IAPP). One tetraquinoline, ADM-116, showed exceptional potency not only in this assay, but also in secondary ... ...

Abstract	An oligoquinoline foldamer library was synthesized and screened for antagonism of lipid bilayer catalysed assembly of islet amyloid polypeptide (IAPP). One tetraquinoline, ADM-116, showed exceptional potency not only in this assay, but also in secondary assays measuring lipid bilayer integrity and rescue of insulin secreting cells from the toxic effects of IAPP. Structure activity studies identified three additional oligoquinolines, closely related to ADM-116, which also have strong activity in the primary, but not the secondary assays. This contrasts work using an oligopyrdyl foldamer scaffold in which all three assays are observed to be correlated. The results suggest that while there is commonality to the structures and pathways of IAPP conformational change, it is nevertheless possible to leverage foldamers to separately affect IAPP's alternative gains-of-function.
MeSH term(s)	Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/toxicity ; Humans ; Insulin-Secreting Cells/drug effects ; Lipid Bilayers/chemistry ; Molecular Structure ; Quinolines/chemical synthesis ; Quinolines/chemistry ; Quinolines/pharmacology
Chemical Substances	Amyloid beta-Peptides ; Lipid Bilayers ; Quinolines ; quinoline (E66400VT9R)
Language	English
Publishing date	2016-04-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/c6cc01248e
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Article ; Online: Common mechanism unites membrane poration by amyloid and antimicrobial peptides.

Last, Nicholas B / Miranker, Andrew D

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 16, Page(s) 6382–6387

Abstract: ... Direct protein-protein interactions cannot be the origin of cooperativity, as IAPP and its enantiomer D ...

Abstract	Poration of bacterial membranes by antimicrobial peptides such as magainin 2 is a significant activity performed by innate immune systems. Pore formation by soluble forms of amyloid proteins such as islet amyloid polypeptide (IAPP) is implicated in cell death in amyloidoses. Similarities in structure and poration activity of these two systems suggest a commonality of mechanism. Here, we investigate and compare the mechanisms by which these peptides induce membrane leakage and bacterial cell death through the measurement of liposome leakage kinetics and bacterial growth inhibition. For both systems, leakage occurs through the nucleation-dependent formation of stable membrane pores. Remarkably, we observe IAPP and magainin 2 to be fully cross-cooperative in the induction of leakage and inhibition of bacterial growth. The effects are dramatic, with mixtures of these peptides showing activities >100-fold greater than simple sums of the activities of individual peptides. Direct protein-protein interactions cannot be the origin of cooperativity, as IAPP and its enantiomer D-IAPP are equally cross-cooperative. We conclude that IAPP and magainin 2 induce membrane leakage and cytotoxicity through a shared, cross-cooperative, tension-induced poration mechanism.
MeSH term(s)	Amino Acid Sequence ; Amyloid/metabolism ; Antimicrobial Cationic Peptides/metabolism ; Cell Membrane/metabolism ; Cell Membrane Permeability/physiology ; Chromatography, High Pressure Liquid ; Circular Dichroism ; Colony Count, Microbial ; Islet Amyloid Polypeptide/metabolism ; Kinetics ; Liposomes/chemistry ; Liposomes/metabolism ; Magainins/metabolism ; Models, Molecular ; Molecular Sequence Data ; Paracoccus denitrificans/growth & development ; Paracoccus denitrificans/metabolism ; Phosphatidylglycerols ; Spectrometry, Fluorescence
Chemical Substances	Amyloid ; Antimicrobial Cationic Peptides ; Islet Amyloid Polypeptide ; Liposomes ; Magainins ; Phosphatidylglycerols ; 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (66322-31-4)
Language	English
Publishing date	2013-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1219059110
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Zs.A 1148: Show issues

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Article ; Online: Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein.

Melissa Birol / Slawomir P Wojcik / Andrew D Miranker / Elizabeth Rhoades

PLoS Biology, Vol 17, Iss 6, p e

2019 Volume 3000318

Abstract	Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively unexplored. Here, we report that αSacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αSun). We identify complex N-linked glycans as binding partners for αSacetyl and demonstrate that cellular internalization of αSacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αSacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αSacetyl. Importantly, our results are specific to αSacetyl because αSun does not demonstrate sensitivity for N-linked glycans in any of our assays. Our study identifies extracellular N-linked glycans-and the glycoprotein neurexin 1β specifically-as key modulators of neuronal uptake of αSacetyl, drawing attention to the potential therapeutic value of αSacetyl-glycan interactions.
Keywords	Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural biology: fibres hinge on swapped domains.

Miranker, Andrew D

Nature

2005 Volume 437, Issue 7056, Page(s) 197–198

MeSH term(s)	Amyloidosis/metabolism ; Dimerization ; Models, Chemical ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Ribonuclease, Pancreatic/chemistry ; Ribonuclease, Pancreatic/genetics ; Ribonuclease, Pancreatic/metabolism ; Solubility ; Thermodynamics
Chemical Substances	Ribonuclease, Pancreatic (EC 3.1.27.5)
Language	English
Publishing date	2005-09-08
Publishing country	England
Document type	Comment ; News
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/437197a
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
Zs.MO 244: Show issues

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Article ; Online: Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

Melissa Birol / Sunil Kumar / Elizabeth Rhoades / Andrew D. Miranker

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 12

Abstract: Toxic gain-of-function by islet amyloid polypeptide (IAPP) is thought to be mediated by membrane poration. Here the authors develop diluted-FRET to show that changes in pore structure correlate with onset of toxicity inside insulin secreting cells. ...

Abstract	Toxic gain-of-function by islet amyloid polypeptide (IAPP) is thought to be mediated by membrane poration. Here the authors develop diluted-FRET to show that changes in pore structure correlate with onset of toxicity inside insulin secreting cells.
Keywords	Science ; Q
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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