Identification of Hot Regions of the Aβ–IAPP Interaction Interface as High‐Affinity Binding Sites in both Cross‐ and Self‐Association

Andreetto, Erika; Yan, Limei; Tatarek‐Nossol, Marianna; Velkova, Aleksandra; Frank, Ronald; Kapurniotu, Aphrodite

doi:10.1002/anie.200904902

Cited by 176 publications

(288 citation statements)

References 38 publications

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“…IAPP inhibits the cytotoxicity of A␤ aggregates at nanomolar concentrations and inhibits A␤ fibrillation at stoichiometric ratios (51). Several small A␤ fragments bind to full-length IAPP, some with nanomolar affinity (52). These results agree with the hypothesis that amyloidal peptides can dissolve amyloid material containing similar sequence motifs (53).…”

Section: Iappsupporting

confidence: 84%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

125

108

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Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

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Section: Iappsupporting

confidence: 84%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

125

108

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“…There have been a number of protein binding partners of A␤ indicated, in particular, the cellular prion protein (15) but also serum amyloid P (SAP) (16), islet amyloid polypeptide (IAPP) (17), and transthyretin (18). The composition of plaques from the brain supports the idea that HSA interacts with a nonfibrillar/monomeric form of A␤ as HSA is not found within plaques, in contrast to serum amyloid P (19).…”

Section: Discussionmentioning

confidence: 93%

Human Serum Albumin Can Regulate Amyloid-β Peptide Fiber Growth in the Brain Interstitium

Stanyon

Viles

2012

Journal of Biological Chemistry

143

124

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“…Especially important here are hydrogen bonds as the architecture of the Identical residues are indicated in red and similar residues in blue. 17 (B) Domains involved in heteroassociation based on structural models of amylin 38 and Aβ fibril models. 62 The amyloid fibrils dependent strongly on an array of inter backbone hydrogen bonds between the β-strands within the core of the fibril.…”

Section: 34mentioning

confidence: 99%

“…On the other hand, the intermolecular electrostatic and the electrostatic solvation terms cancel each other and contribute little to the association of the three oligomer systems. The per-residue energy decomposition of the nonpolar van der Waals interactions shows that the stabilizing contributions come from hydrophobic residues that are involved in the face-to-face intrastrand and interstrand interactions of all three oligomers (i.e., L 17 10−35 ; combination of these key amino acids in the Aβ 15−40 |amylin 10−35 heteroassembly) through nonpolar contacts between main chains and side chains.…”

mentioning

confidence: 99%

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

Berhanu

Yaşar

Hansmann

2013

ACS Chem. Neurosci.

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Recent epidemiological data have shown that patients suffering from Type 2 Diabetes Mellitus have an increased risk to develop Alzheimer's disease and vice versa. A possible explanation is the cross-sequence interaction between Aβ and amylin. Because the resulting amyloid oligomers are difficult to probe in experiments, we investigate stability and conformational changes of Aβ−amylin heteroassemblies through molecular dynamics simulations. We find that Aβ is a good template for the growth of amylin and vice versa. We see water molecules permeate the β-strand−turn−β-strand motif pore of the oligomers, supporting a commonly accepted mechanism for toxicity of β-rich amyloid oligomers. Aiming for a better understanding of the physical mechanisms of cross-seeding and cell toxicity of amylin and Aβ aggregates, our simulations also allow us to identify targets for the rational design of inhibitors against toxic fibril-like oligomers of Aβ and amylin oligomers.

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Identification of Hot Regions of the Aβ–IAPP Interaction Interface as High‐Affinity Binding Sites in both Cross‐ and Self‐Association

Cited by 176 publications

References 38 publications

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Human Serum Albumin Can Regulate Amyloid-β Peptide Fiber Growth in the Brain Interstitium

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

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