Role of cholesterol in substrate recognition by $$\gamma$$-secretase

Abstract

Abstract$$\gamma$$ γ -Secretase is an enzyme known to cleave multiple substrates within their transmembrane domains, with the amyloid precursor protein of Alzheimer’s Disease among the most prominent examples. The activity of $$\gamma$$ γ -secretase strictly depends on the membrane cholesterol content, yet the mechanistic role of cholesterol in the substrate binding and cleavage remains unclear. In this work, we used all-atom molecular dynamics simulations to examine the role of cholesterol in the initial binding of a direct precursor of $$\beta$$ β -amyloid polypeptides by $$\gamma$$ γ -secretase. We showed that in cholesterol-rich membranes, both the substrate and the enzyme region proximal to the active site induce a local membrane thinning. With the free energy methods we found that in the presence of cholesterol the substrate binds favorably to the identified exosite, while cholesterol depletion completely abolishes the binding. To explain these findings, we directly examined the role of hydrophobic mismatch in the substrate binding to $$\gamma$$ γ -secretase, showing that increased membrane thickness results in higher propensity of the enzyme to bind substrates. Therefore, we propose that cholesterol promotes substrate binding to $$\gamma$$ γ -secretase by increasing the membrane thickness, which leads to the negative hydrophobic mismatch between the membrane and binding partners.

Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease

“…For amyloidogenic cleavage, the APP must be colocalized in a cholesterol-dependent manner with β- and γ-secretases in the intracellular lipid raft membrane (Ehehalt et al, 2003 ; von Arnim et al, 2008 ; Area-Gomez et al, 2009 ; Cossec et al, 2010 ; Panahi et al, 2016 ; Chung et al, 2018 ; DelBove et al, 2019 ). Since cholesterol interacts directly with APP and secretase actions also depend on cholesterol, the cleavage of APP and the resulting amyloid production are strongly linked to the amount of cholesterol and its membrane distribution (Marquer et al, 2011 ; Barrett et al, 2012 ; Decock et al, 2015 ; Kim et al, 2016 ; Sun et al, 2017 ; Audagnotto et al, 2018 ; Agrawal et al, 2020 ; Montesinos et al, 2020 ; Pantelopulos et al, 2020 ; Nierzwicki et al, 2021 ).…”

Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol

“…By forming lipid rafts, cholesterol creates optimal conditions for β- and γ-secretase activity [ 54 , 165 , 174 , 201 , 210 , 223 , 227 , 297 – 299 ]. Cholesterol makes the active site γ-secretase more compact and supports secretase activity toward C99, which promotes Aβ42 generation [ 239 , 300 ]. All four parts of the γ-secretase complex contain common TM cholesterol binding motifs CARC or CRAC [ 239 , 301 ].…”

Role of Mitochondrial Protein Import in Age-Related Neurodegenerative and Cardiovascular Diseases

“…Mitochondrial membranes contain relatively low amounts of cholesterol, but these changes are important [ 57 , 58 ]. Cholesterol affects the Aβ maturation, directly influencing the activity of γ-secretase in MAM during proteolytic degradation of amyloid precursor protein (APP) [ 126 , 127 , 128 ]. Cholesterol also interacts with the membrane part of APP [ 129 , 130 ], affects the activity of β-secretase [ 131 , 132 ] and α-secretase [ 133 ], defining the sequential cleavage of APP either via the amyloidogenic or non-amyloidogenic pathway, respectively.…”