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Comments on Paper and Primary News |
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Comment by: Brigita Urbanc, ARF Advisor
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Submitted 22 October 2007
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Posted 22 October 2007
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A New Alternative "Endosomic" Amyloid Hypothesis?
Amyloid β-protein (Aβ), which is believed to play a critical role at early stages of Alzheimer disease (AD), belongs to the group of natively unfolded proteins. Aβ is known to adopt a collapsed coil folded structure in water, whereas in a co-solvent TFE, which is known to stabilize hydrogen bonding, a pH-dependent α-helical folded structure has been found. Another reason why the pH-dependence is important to understand has to do with the fact that different cellular versus extracellular compartments, where Aβ might be present, have different pH values. Specifically, the extracellular environment is typically characterized by a normal pH = 7.4, while early endosomes (compartments inside the cell) have slightly acidic conditions corresponding to pH = 6. Where the earliest events in Aβ assembly take place, inside the cell, outside the cell, or within a cellular membrane, has been an active research topic for many years. Thus, understanding Aβ folding in different...
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Comments on Related News |
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Related News: Shaping Up Amyloid Toxicity: Does It Compute?
Comment by: David Teplow
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Submitted 27 November 2007
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Posted 27 November 2007
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On Computers, Flies, and Alzheimer Disease
Two recently published papers address the fundamental question of how amyloid proteins form neurotoxic assemblies (see Luheshi et al., 2007 and Cheon et al., 2007). Pat McCaffrey has written an informative and insightful news report that summarizes their key findings and implications. The work reported extends efforts by the ”Cambridge group” (broadly defined, and including those in Firenze, Italy; Busan, Korea; and Jülich, Germany) to explore ”generic” protein folding pathways and their biological consequences. In these latest publications, the group extends the idea of generic protein structures to generic toxicity, meaning that protein assemblies that share structural features also share toxic activity. Importantly, algorithms have been developed that allow prediction of assembly state and neurotoxicity from protein primary structure.
The technical rigor of the two studies is excellent. Thus, within the contexts of the...
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Related News: Shaping Up Amyloid Toxicity: Does It Compute?
Comment by: Leila Luheshi
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Submitted 20 December 2007
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Posted 21 December 2007
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Reply by Leila M. Luheshi, Giorgio Favrin, Damian C. Crowther, Michele Vendruscolo, and Christopher M. Dobson to Teplow Comment
We are pleased to have the opportunity of adding further observations to a recent commentary by David Teplow about the “generic hypothesis” of amyloid fibril formation (1). According to this hypothesis, the ability to form amyloid structures is an inherent property of polypeptide chains, although the propensity to form such structures can vary dramatically with their sequences (2).
This hypothesis is supported by a growing body of experimental evidence that has been summarized in a number of recent reviews (3). The generic nature of amyloid fibrils resides in their core cross-β structure, which is stabilized predominantly by backbone hydrogen bonding interactions (4). It has also been recently discovered that the range of proteins capable of forming toxic oligomers, that may well be precursors to mature amyloid fibrils, is very large and includes those with no known association with disease (5-7). Of course, there are many...
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Related News: Affibodies—Putting the β in Aβ?
Comment by: Chris Dealwis
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Submitted 20 March 2008
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Posted 20 March 2008
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Hoyer and coworkers have solved a structure of the amyloid-β peptide in complex with a phage-display selected affibody using NMR spectroscopy. The affibody is responsible for stabilizing the Aβ monomer by inhibiting fibril formation. The Aβ adopts a parallel β-hairpin structure, where the two β-strands consisting of residues 15-22 (strand A) and 30-36 (strand B) form intramolecular hydrogen bonds between each other. Strand A is stabilized by a short strand from the affibody which runs anti-parallel, while strand B is stabilized by a short strand that is parallel to it.
From a large body of data, we know that fibrils exhibit a “cross-β” pattern in x-ray fiber diffraction (1). This is associated with a fundamental structure consisting of extended β-sheet networks in which peptide chains are displayed perpendicular to the fibril axis, while the hydrogen bonding direction of the sheet is parallel to the fibril axis (2,3). Hence, the direction of the hydrogen bonds of a conventional β-hairpin as observed in the current study will not fit...
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Related News: Affibodies—Putting the β in Aβ?
Comment by: Brigita Urbanc, ARF Advisor
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Submitted 9 April 2008
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Posted 9 April 2008
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Capturing Aβ Using Engineered Affinity Proteins
Alzheimer disease (AD) is associated with the amyloid-β protein (Aβ) which assembles into toxic oligomers, protofibrils, and fibrils, and is the major component of amyloid plaques in the AD brain. Substantial evidence implicates the early stages of Aβ assembly in the onset of the disease. Many different strategies that aim at preventing Aβ molecules from formation of toxic assemblies are currently under investigation.
The present study by Hoyer et al. was motivated by novel therapeutic strategies that explore ways to create a peripheral sink mechanism by administering an Aβ binding molecule, a ligand, with the capacity to reduce Aβ in the central nervous system by channeling it into the plasma. As the Aβ1-40 binding molecule, Hoyer et al. proposed to apply an engineered affinity protein (affibody), ZAβ3, based on the Z domain derived from the staphylococcal protein A. In their paper, Hoyer et al. presented 16 different ligands which were previously shown to bind both...
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