title: Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1.
abstract: Presenilin 1 (PS1) is the catalytic unit of γ-secretase which cleaves more than one hundred substrates. Among them, amyloid precursor protein (APP) and Notch are notable for their pivotal role in the pathogenesis of Alzheimer's disease (AD) and certain types of cancer. The hydrolysis process occurring inside the hydrophobic lipid bilayer remains unclear. With the aim to understand the mechanism of intramembrane proteolysis by γ-secretase, we constructed a homology model of human PS1 and performed molecular dynamics simulation in explicit membrane phospholipids with different components. During the simulation, TM9 was found to exhibit a high level of flexibility that involved in "gate-open" movement of TM2 and TM6, and thus partially exposed the catalytic residues. The highly conserved PALP motif acts as an anchor to mediate the conformation changes of TM6 induced by TM9. Moreover, direct interactions were observed between 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and the active site of γ-secretase, indicating that the lipid molecules have the potential to modulate γ-secretase by contacting with the catalytic residues, i.e., ASP 257 and ASP 385 of PS1. The intermediate states indicate a potential substrate penetration pathway through the interface of TM2 and TM6, which may be induced by changes of TM9. To our knowledge, this is the first molecular simulation study that reveals dynamic behavior of the human PS1 structure in the lipid bilayer and provides insight into the substrate entry path for subsequent intramembrane hydrolysis, which is critical information required for new strategy development of γ-secretase modulators to alleviate devastating AD.
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA; Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Kong
authors.affiliation: Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Veterans Affairs, Medical Research & Development Service and Geriatric Research, Education and Clinical Center, Bedford, MA, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA. Electronic address: stwong@houstonmethodist.org.
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D053764:Presenilin-1 / Q000737:chemistry*; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
keywords: Membrane protein; Molecular dynamics simulation; Presenilin-1; γ-Secretase