Understanding familial Alzheimer's disease: The fit‐stay‐trim mechanism of γ‐secretase

Abstract

Understanding Alzheimer's disease is a central challenge of the 21st century, as the disease affects tens of millions of people and kills a million people each year, with current drugs having modest effect. This article reviews how computational science integrating new cryo‐electron microscopy structures and biochemical and clinical data has led to a causative model of familial Alzheimer's disease (fAD). The model's basis is open and compact conformational states of the membrane protease γ‐secretase, controlled by transmembrane helix “fingers” that hold the substrate either tightly or loosely. The two states are in thermal equilibrium and lead to different amounts of long and short Aβ peptides, explaining the much‐debated Aβ42/Aβ40 ratio. Pathogenic mutations shift the equilibrium toward the open state by reducing the stability and hydrophobic packing of the enzyme‐substrate complex, which increases toxic Aβ42 and other longer peptide forms compared with Aβ40. In contrast, drugs that selectively target longer, pathogenic Aβ peptides should preferentially stabilize the compact state to reverse this tendency. The model may explain how inherited mutations cause fAD and provides a molecular roadmap for the development of γ‐secretase modulators, one of the most promising causative treatment strategies in current Alzheimer research. In summary, we showcase the power of modern multiscale computational science in integrating biochemical, protein‐structural, and clinical data to elucidate complex disease mechanisms. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Data Science > Chemoinformatics

Effects of presenilin-1 familial Alzheimer’s disease mutations on γ-secretase activation for cleavage of amyloid precursor protein

“…The free energy landscapes and low-energy conformational states were explored in detail, which allowed us to deduce the effects of PS1 FAD mutants on the proteolytic activity of γ-secretase. Here, our main conclusion was that the PS1 FAD mutant γ-secretase stabilized the active sites of the enzyme-substrate complexes, which was distinctly different from previous studies, which suggested that PS1 FAD mutants destabilized the enzyme-substrate complexes, causing the earlier releases of longer Aβ peptides 10 , 22 , 42 – 45 .…”

“…As the APP substrate was properly located inside the active site, its β3 strand (involving APP residues M51–K53) was formed through the hydrogen bonds with the β2 strand connected to PS1 TM7 (involving PS1 residues V379–L381) 50 . This finding was highly consistent with previous simulation studies, in which the repeated formations of β-strands in several solvent-exposed regions of presenilin were observed 22 , 43 , 51 , 52 . Afterwards, the catalytic aspartates D257 and D385 drew closer to each other, at a ~7–8 Å distance in the “Active” conformation, to recruit a water molecule poised for the proteolytic reaction (Fig.…”

“…6 ). Nevertheless, it was worth noting that the β3 strand of APP was formed in all three “Active” low-energy conformations (WT, P117L, and L286V), being consistent with previous studies 22 , 43 , 51 , 52 .…”

“…Molecular dynamics (MD) is a powerful computational technique for simulating biomolecular dynamics at an atomistic level 19 . Kong et al 20 performed the first atomistic simulation of isolated PS1 unit in 2015 and found that transmembrane domains (TM) 2, 6, and 9 were highly mobile 21 , 22 . In addition, only inactive distances between catalytic aspartates were sampled in the study because of the electrostatic repulsion caused by the negative charges of the two aspartates forming the active site 20 , 21 .…”

Enzyme–substrate interface targeting by imidazole‐based γ‐secretase modulators activates γ‐secretase and stabilizes its interaction withAPP

“…Our in silico analyses showing the coherent conversion of the GSM-GSEC-APP into the GSM-GSEC complex suggest the possibility that an equilibrium between these complexes exists and is regulated by the relative concentrations of the GSM and GSEC substrates. This strengthens the high pathophysiological relevance of protein dynamics in the regulation of GSEC function (Ch avez-Guti errez & Szaruga, 2020;Mehra & Kepp, 2021).…”