Abstract
Besides amyloid fibrils, amyloid pores (APs) represent another mechanism of amyloid induced toxicity. Since hypothesis put forward by Arispe and collegues in 1993 that amyloid-beta makes ion-conducting channels and that Alzheimer's disease may be due to the toxic effect of these channels, many studies have confirmed that APs are formed by prefibrillar oligomers of amyloidogenic proteins and are a common source of cytotoxicity. The mechanism of pore formation is still not well-understood and the structure and imaging of APs in living cells remains an open issue. To get closer to understand AP formation we used predictive methods to assess the propensity of a set of 30 amyloid-forming proteins (AFPs) to form transmembrane channels. A range of amino-acid sequence tools were applied to predict AP domains of AFPs, and provided context on future experiments that are needed in order to contribute toward a deeper understanding of amyloid toxicity. In a set of 30 AFPs we predicted their amyloidogenic propensity, presence of transmembrane (TM) regions, and cholesterol (CBM) and ganglioside binding motifs (GBM), to which the oligomers likely bind. Noteworthy, all pathological AFPs share the presence of TM, CBM, and GBM regions, whereas the functional amyloids seem to show just one of these regions. For comparative purposes, we also analyzed a few examples of amyloid proteins that behave as biologically non-relevant AFPs. Based on the known experimental data on the β-amyloid and α-synuclein pore formation, we suggest that many AFPs have the potential for pore formation. Oligomerization and α-TM helix to β-TM strands transition on lipid rafts seem to be the common key events.
Highlights
It is widely accepted and inherited cases confirm a notion that the major part of the pathology of neurodegenerative diseases is due to aberrant processes of protein misfolding and formation of amyloid fibrils by the amyloidogenic proteins concerned: α-synuclein in Parkinson’s disease, β-amyloid (Aβ) in Alzheimer’s disease, SOD1 and transactive response DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis, etc.Prediicting Amyloid Membrane InteractionDobson (2002) discovered that these conformational transitions are not reserved to amyloidogenic proteins, but that under certain conditions all proteins can be converted into amyloid fibrils, even the very stable and α-helical myoglobin (Fandrich et al, 2001)
Dobson (2002) discovered that these conformational transitions are not reserved to amyloidogenic proteins, but that under certain conditions all proteins can be converted into amyloid fibrils, even the very stable and α-helical myoglobin (Fandrich et al, 2001)
Amyloidogenic proteins do not have common sequence motifs, but by comparing the protein sequences it can be predicted that some parts are hot spots that form a cross-β spine of amyloid-like fibrils (Nelson et al, 2005)
Summary
Dobson (2002) discovered that these conformational transitions are not reserved to amyloidogenic proteins, but that under certain conditions all proteins can be converted into amyloid fibrils, even the very stable and α-helical myoglobin (Fandrich et al, 2001). The tendency to misfold and aggregate to amyloid at physiological pH and temperature is not the same for all proteins; certain proteins or their parts—after cleavage—are more susceptible to the formation of amyloid fibrils. Amyloidogenic proteins do not have common sequence motifs, but by comparing the protein sequences it can be predicted that some parts are hot spots that form a cross-β spine of amyloid-like fibrils (Nelson et al, 2005). The secondary structure in the native fold protein is important, but not directly correlated with the secondary structure of the amyloid fibrils. The overprediction of α-helices compared to the X-ray structure derived α-helices indicates the propensity of α to β transition in the intermediate (Morillas et al, 2001), partially unfolded state and, for intrinsically disordered proteins, partially folded state
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