Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1

doi:10.1016/j.jsb.2015.07.001

. 2015 Aug;191(2):120-9.

doi: 10.1016/j.jsb.2015.07.001. Epub 2015 Jul 2.

Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1

Ren Kong¹, Shan Chang², Weiming Xia³, Stephen T C Wong⁴

Affiliations

¹ 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.
² Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
³ Department of Veterans Affairs, Medical Research & Development Service and Geriatric Research, Education and Clinical Center, Bedford, MA, USA.
⁴ Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA. Electronic address: stwong@houstonmethodist.org.

PMID: 26142917
DOI: 10.1016/j.jsb.2015.07.001

Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1

Ren Kong et al. J Struct Biol. 2015 Aug.

. 2015 Aug;191(2):120-9.

doi: 10.1016/j.jsb.2015.07.001. Epub 2015 Jul 2.

Authors

Ren Kong¹, Shan Chang², Weiming Xia³, Stephen T C Wong⁴

Affiliations

¹ 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.
² Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, China.
³ Department of Veterans Affairs, Medical Research & Development Service and Geriatric Research, Education and Clinical Center, Bedford, MA, USA.
⁴ Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA. Electronic address: stwong@houstonmethodist.org.

PMID: 26142917
DOI: 10.1016/j.jsb.2015.07.001

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.

Keywords: Membrane protein; Molecular dynamics simulation; Presenilin-1; γ-Secretase.

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Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1

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Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1

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