Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer's disease

Abstract

Significancepathogenic changes in {gamma}-secretase activity, and its response to different drugs, can be greatly affected by changes in saturation of {gamma}-secretase with its substrate. The molecular mechanism is unclear. Resultsmultiscale molecular dynamics studies show that saturation of {gamma}-secretase with its substrate can result in parallel binding of different substrate molecules at the docking site and the active site. C-terminal domain of the second substrate can bind at cytosolic end of presenilin subunit while {gamma}-secretase is still processing its first substrate. Such interactions can disrupt dynamic presenilin structures that regulate proteolytic steps. Similar disruptions in dynamic presenilin structures can be produced by different drugs and by different disease-causing mutations. Thus, the presented two-substrate mechanism, can explain toxic inhibition of {gamma}-secretase activity and toxic increase in production of the longer, more hydrophobic, A{beta}-proteins. Toxic aggregation between N-terminal domains of the two substrates is controlled by nicastrin ectodomain. Such aggregation is more likely to happen with C99-{beta}CTF-APP than with C83-CTF-APP substrate, which can explain, why {beta}-secretase path is more pathogenic than -secretase path. The binding of C99-{beta}CTF-APP substrate to {gamma}-secretase can be controlled by substrate-channeling between nicastrin ectodomain and {beta}-secretase. ConclusionsThe presented two-substrate mechanism can explain why different studies consistently show that increase in saturation of {gamma}-secretase with its substrate can support pathogenic changes in different sporadic and familiar cases of the disease. Future drug-development strategies can target different physiological mechanisms that control the balance between cellular levels of {gamma}-secretase activity and the total amyloid metabolism.