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

Do, Hung N.; Devkota, Sujan; Bhattarai, Apurba; Wolfe, Michael S.; Miao, Yinglong

doi:10.1038/s42003-023-04539-1

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

Journal Article · Mon Feb 13 23:00:00 EST 2023 · Communications Biology

DOI:https://doi.org/10.1038/s42003-023-04539-1· OSTI ID:2422941

^[1]; Devkota, Sujan ^[1]; Bhattarai, Apurba ^[1]; ^[1]; ^[1]

Univ. of Kansas, Lawrence, KS (United States)

Presenilin-1 (PS1) is the catalytic subunit of γ-secretase which cleaves within the transmembrane domain of over 150 peptide substrates. Dominant missense mutations in PS1 cause early-onset familial Alzheimer’s disease (FAD); however, the exact pathogenic mechanism remains unknown. Here we combined Gaussian accelerated molecular dynamics (GaMD) simulations and biochemical experiments to determine the effects of six representative PS1 FAD mutations (P117L, I143T, L166P, G384A, L435F, and L286V) on the enzyme-substrate interactions between γ-secretase and amyloid precursor protein (APP). Biochemical experiments showed that all six PS1 FAD mutations rendered γ-secretase less active for the endoproteolytic (ε) cleavage of APP. Distinct low-energy conformational states were identified from the free energy profiles of wildtype and PS1 FAD-mutant γ-secretase. The P117L and L286V FAD mutants could still sample the “Active” state for substrate cleavage, but with noticeably reduced conformational space compared with the wildtype. The other mutants hardly visited the “Active” state. The PS1 FAD mutants were found to reduce γ-secretase proteolytic activity by hindering APP residue L49 from proper orientation in the active site and/or disrupting the distance between the catalytic aspartates. Therefore, our findings provide mechanistic insights into how PS1 FAD mutations affect structural dynamics and enzyme-substrate interactions of γ-secretase and APP.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE; National Science Foundation (NSF); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2422941

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 6; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

References (68)

CHARMM-GUI: A web-based graphical user interface for CHARMM Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G. Journal of Computational Chemistry, Vol. 29, Issue 11 https://doi.org/10.1002/jcc.20945	journal	March 2008
CHARMM: The biomolecular simulation program Brooks, B. R.; Brooks, C. L.; Mackerell, A. D. Journal of Computational Chemistry, Vol. 30, Issue 10 https://doi.org/10.1002/jcc.21287	journal	July 2009
CHARMM-GUI Membrane Builder toward realistic biological membrane simulations Wu, Emilia L.; Cheng, Xi; Jo, Sunhwan Journal of Computational Chemistry, Vol. 35, Issue 27 https://doi.org/10.1002/jcc.23702	journal	August 2014
Gaussian accelerated molecular dynamics: Principles and applications Wang, Jinan; Arantes, Pablo R.; Bhattarai, Apurba WIREs Computational Molecular Science, Vol. 11, Issue 5 https://doi.org/10.1002/wcms.1521	journal	March 2021
Understanding familial Alzheimer's disease: The fit‐stay‐trim mechanism of γ‐secretase Mehra, Rukmankesh; Kepp, Kasper Planeta WIREs Computational Molecular Science, Vol. 12, Issue 1 https://doi.org/10.1002/wcms.1556	journal	June 2021
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: Evidence that an initially deposited species is Aβ42(43) Iwatsubo, Takeshi; Odaka, Asano; Suzuki, Nobuhiro Neuron, Vol. 13, Issue 1 https://doi.org/10.1016/0896-6273(94)90458-8	journal	July 1994
Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration Saura, Carlos A.; Choi, Se-Young; Beglopoulos, Vassilios Neuron, Vol. 42, Issue 1 https://doi.org/10.1016/S0896-6273(04)00182-5	journal	April 2004
CHARMM-GUI Membrane Builder for Mixed Bilayers and Its Application to Yeast Membranes Jo, Sunhwan; Lim, Joseph B.; Klauda, Jeffery B. Biophysical Journal, Vol. 97, Issue 1 https://doi.org/10.1016/j.bpj.2009.04.013	journal	July 2009
The Amyloid State of Proteins in Human Diseases Eisenberg, David; Jucker, Mathias Cell, Vol. 148, Issue 6 https://doi.org/10.1016/j.cell.2012.02.022	journal	March 2012
Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions Szaruga, Maria; Munteanu, Bogdan; Lismont, Sam Cell, Vol. 170, Issue 3 https://doi.org/10.1016/j.cell.2017.07.004	journal	July 2017
Structural basis of γ-secretase inhibition and modulation by small molecule drugs Yang, Guanghui; Zhou, Rui; Guo, Xuefei Cell, Vol. 184, Issue 2 https://doi.org/10.1016/j.cell.2020.11.049	journal	January 2021
γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43 Okochi, Masayasu; Tagami, Shinji; Yanagida, Kanta Cell Reports, Vol. 3, Issue 1 https://doi.org/10.1016/j.celrep.2012.11.028	journal	January 2013
Familial Alzheimer’s disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues Devkota, Sujan; Williams, Todd D.; Wolfe, Michael S. Journal of Biological Chemistry, Vol. 296 https://doi.org/10.1016/j.jbc.2021.100281	journal	January 2021
Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1 Kong, Ren; Chang, Shan; Xia, Weiming Journal of Structural Biology, Vol. 191, Issue 2 https://doi.org/10.1016/j.jsb.2015.07.001	journal	August 2015
A computer-simulated mechanism of familial Alzheimer’s disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase Dehury, Budheswar; Somavarapu, Arun K.; Kepp, Kasper P. Journal of Structural Biology, Vol. 212, Issue 3 https://doi.org/10.1016/j.jsb.2020.107648	journal	December 2020
The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access Somavarapu, Arun Kumar; Kepp, Kasper P. Neurobiology of Disease, Vol. 89 https://doi.org/10.1016/j.nbd.2016.02.008	journal	May 2016
Familial Alzheimer’s Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds Veugelen, Sarah; Saito, Takashi; Saido, Takaomi C. Neuron, Vol. 90, Issue 2 https://doi.org/10.1016/j.neuron.2016.03.010	journal	April 2016
Structure and mechanism of the γ-secretase intramembrane protease complex Wolfe, Michael S.; Miao, Yinglong Current Opinion in Structural Biology, Vol. 74 https://doi.org/10.1016/j.sbi.2022.102373	journal	June 2022
The dynamics of γ-secretase and its substrates Hitzenberger, Manuel; Götz, Alexander; Menig, Simon Seminars in Cell & Developmental Biology, Vol. 105 https://doi.org/10.1016/j.semcdb.2020.04.008	journal	September 2020
The substrate repertoire of γ-secretase/presenilin Güner, Gökhan; Lichtenthaler, Stefan F. Seminars in Cell & Developmental Biology, Vol. 105 https://doi.org/10.1016/j.semcdb.2020.05.019	journal	September 2020
Structure and Function of the γ-Secretase Complex Wolfe, Michael S. Biochemistry, Vol. 58, Issue 27 https://doi.org/10.1021/acs.biochem.9b00401	journal	June 2019
Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation Miao, Yinglong; Feher, Victoria A.; McCammon, J. Andrew Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00436	journal	July 2015
CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field Lee, Jumin; Cheng, Xi; Swails, Jason M. Journal of Chemical Theory and Computation, Vol. 12, Issue 1 https://doi.org/10.1021/acs.jctc.5b00935	journal	December 2015
CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans Lee, Jumin; Patel, Dhilon S.; Ståhle, Jonas Journal of Chemical Theory and Computation, Vol. 15, Issue 1 https://doi.org/10.1021/acs.jctc.8b01066	journal	November 2018
Mechanisms of γ-Secretase Activation and Substrate Processing Bhattarai, Apurba; Devkota, Sujan; Bhattarai, Sanjay ACS Central Science, Vol. 6, Issue 6 https://doi.org/10.1021/acscentsci.0c00296	journal	June 2020
How Mutations Perturb γ-Secretase Active Site Studied by Free Energy Simulations Chen, Shu-Yu; Zacharias, Martin ACS Chemical Neuroscience, Vol. 11, Issue 20 https://doi.org/10.1021/acschemneuro.0c00440	journal	September 2020
Membrane Dynamics of γ-Secretase Provides a Molecular Basis for β-Amyloid Binding and Processing Somavarapu, Arun Kumar; Kepp, Kasper P. ACS Chemical Neuroscience, Vol. 8, Issue 11 https://doi.org/10.1021/acschemneuro.7b00208	journal	August 2017
Follow the Protons: A Low-Barrier Hydrogen Bond Unifies the Mechanisms of the Aspartic Proteases Northrop, Dexter B. Accounts of Chemical Research, Vol. 34, Issue 10 https://doi.org/10.1021/ar000184m	journal	October 2001
Dissociation between the Processivity and Total Activity of γ-Secretase: Implications for the Mechanism of Alzheimer's Disease-Causing Presenilin Mutations Quintero-Monzon, Omar; Martin, Morgan M.; Fernandez, Marty A. Biochemistry, Vol. 50, Issue 42 https://doi.org/10.1021/bi2007146	journal	September 2011
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K _a Predictions Olsson, Mats H. M.; Søndergaard, Chresten R.; Rostkowski, Michal Journal of Chemical Theory and Computation, Vol. 7, Issue 2 https://doi.org/10.1021/ct100578z	journal	December 2010
Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K _a Values Søndergaard, Chresten R.; Olsson, Mats H. M.; Rostkowski, Michał Journal of Chemical Theory and Computation, Vol. 7, Issue 7 https://doi.org/10.1021/ct200133y	journal	June 2011
Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald Salomon-Ferrer, Romelia; Götz, Andreas W.; Poole, Duncan Journal of Chemical Theory and Computation, Vol. 9, Issue 9 https://doi.org/10.1021/ct400314y	journal	August 2013
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data Roe, Daniel R.; Cheatham, Thomas E. Journal of Chemical Theory and Computation, Vol. 9, Issue 7 https://doi.org/10.1021/ct400341p	journal	June 2013
Improved Reweighting of Accelerated Molecular Dynamics Simulations for Free Energy Calculation Miao, Yinglong; Sinko, William; Pierce, Levi Journal of Chemical Theory and Computation, Vol. 10, Issue 7 https://doi.org/10.1021/ct500090q	journal	May 2014
Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase Bhattarai, Apurba; Devkota, Sujan; Do, Hung Nguyen Journal of the American Chemical Society, Vol. 144, Issue 14 https://doi.org/10.1021/jacs.1c10533	journal	April 2022
Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity Wolfe, Michael S.; Xia, Weiming; Ostaszewski, Beth L. Nature, Vol. 398, Issue 6727 https://doi.org/10.1038/19077	journal	April 1999
The mechanism of γ-Secretase dysfunction in familial Alzheimer disease Chávez-Gutiérrez, Lucía; Bammens, Leen; Benilova, Iryna The EMBO Journal, Vol. 31, Issue 10 https://doi.org/10.1038/emboj.2012.79	journal	April 2012
An atomic structure of human γ-secretase Bai, Xiao-chen; Yan, Chuangye; Yang, Guanghui Nature, Vol. 525, Issue 7568 https://doi.org/10.1038/nature14892	journal	August 2015
CHARMM36m: an improved force field for folded and intrinsically disordered proteins Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz Nature Methods, Vol. 14, Issue 1 https://doi.org/10.1038/nmeth.4067	journal	November 2016
γ-Secretase: proteasome of the membrane? Kopan, Raphael; Ilagan, Ma. Xenia G. Nature Reviews Molecular Cell Biology, Vol. 5, Issue 6 https://doi.org/10.1038/nrm1406	journal	June 2004
Molecular dynamics simulations of biomolecules Karplus, Martin; McCammon, J. Andrew Nature Structural Biology, Vol. 9, Issue 9 https://doi.org/10.1038/nsb0902-646	journal	September 2002
Structural basis of Notch recognition by human γ-secretase Yang, Guanghui; Zhou, Rui; Zhou, Qiang Nature, Vol. 565, Issue 7738 https://doi.org/10.1038/s41586-018-0813-8	journal	December 2018
A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase Lu, Xiaoli; Huang, Jing Communications Biology, Vol. 5, Issue 1 https://doi.org/10.1038/s42003-022-03818-7	journal	August 2022
Characterizing the structural ensemble of γ-secretase using a multiscale molecular dynamics approach Aguayo-Ortiz, Rodrigo; Chávez-García, Cecilia; Straub, John E. Chemical Science, Vol. 8, Issue 8 https://doi.org/10.1039/C7SC00980A	journal	January 2017
Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature Dehury, Budheswar; Tang, Ning; Mehra, Rukmankesh RSC Advances, Vol. 10, Issue 52 https://doi.org/10.1039/D0RA04683C	journal	January 2020
CHARMM-GUI supports the Amber force fields Lee, Jumin; Hitzenberger, Manuel; Rieger, Manuel The Journal of Chemical Physics, Vol. 153, Issue 3 https://doi.org/10.1063/5.0012280	journal	July 2020
The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism Shen, Jie; Kelleher, Raymond J. Proceedings of the National Academy of Sciences, Vol. 104, Issue 2 https://doi.org/10.1073/pnas.0608332104	journal	January 2007
Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state Li, Yue-Ming; Lai, Ming-Tain; Xu, Min Proceedings of the National Academy of Sciences, Vol. 97, Issue 11 https://doi.org/10.1073/pnas.110126897	journal	May 2000
Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ ₄₂ production Moehlmann, Tobias; Winkler, Edith; Xia, Xuefeng Proceedings of the National Academy of Sciences, Vol. 99, Issue 12 https://doi.org/10.1073/pnas.112686799	journal	June 2002
Structural basis of human γ-secretase assembly Sun, Linfeng; Zhao, Lingyun; Yang, Guanghui Proceedings of the National Academy of Sciences, Vol. 112, Issue 19 https://doi.org/10.1073/pnas.1506242112	journal	April 2015
A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of γ-Secretase Activity Heilig, Elizabeth A.; Xia, Weiming; Shen, Jie Journal of Biological Chemistry, Vol. 285, Issue 29 https://doi.org/10.1074/jbc.M110.116962	journal	July 2010
Alzheimer Presenilin-1 Mutations Dramatically Reduce Trimming of Long Amyloid β-Peptides (Aβ) by γ-Secretase to Increase 42-to-40-Residue Aβ Fernandez, Marty A.; Klutkowski, Julia A.; Freret, Taylor Journal of Biological Chemistry, Vol. 289, Issue 45 https://doi.org/10.1074/jbc.M114.581165	journal	November 2014
Potential Link between Amyloid β-Protein 42 and C-terminal Fragment γ 49–99 of β-Amyloid Precursor Protein Sato, Toru; Dohmae, Naoshi; Qi, Yue Journal of Biological Chemistry, Vol. 278, Issue 27 https://doi.org/10.1074/jbc.M211161200	journal	July 2003
Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides Nakaya, Yoshifumi; Yamane, Takuya; Shiraishi, Hirohisa Journal of Biological Chemistry, Vol. 280, Issue 19 https://doi.org/10.1074/jbc.M501130200	journal	May 2005
The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Aβ42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants Saura, Carlos A.; Tomita, Taisuke; Soriano, Salvador Journal of Biological Chemistry, Vol. 275, Issue 22 https://doi.org/10.1074/jbc.M909624199	journal	June 2000
SWISS-MODEL: homology modelling of protein structures and complexes Waterhouse, Andrew; Bertoni, Martino; Bienert, Stefan Nucleic Acids Research, Vol. 46, Issue W1 https://doi.org/10.1093/nar/gky427	journal	May 2018
The Genetics of Alzheimer Disease Tanzi, R. E. Cold Spring Harbor Perspectives in Medicine, Vol. 2, Issue 10 https://doi.org/10.1101/cshperspect.a006296	journal	July 2012
Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's disease Somavarapu, Arun Kumar; Kepp, Kasper P. Journal of Neurochemistry, Vol. 137, Issue 1 https://doi.org/10.1111/jnc.13535	journal	February 2016
Recognition of the amyloid precursor protein by human γ-secretase Zhou, Rui; Yang, Guanghui; Guo, Xuefei Science, Vol. 363, Issue 6428 https://doi.org/10.1126/science.aaw0930	journal	January 2019
Automated Builder and Database of Protein/Membrane Complexes for Molecular Dynamics Simulations Jo, Sunhwan; Kim, Taehoon; Im, Wonpil PLoS ONE, Vol. 2, Issue 9 https://doi.org/10.1371/journal.pone.0000880	journal	September 2007
-Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of -Carboxyl Terminal Fragment Takami, M.; Nagashima, Y.; Sano, Y. Journal of Neuroscience, Vol. 29, Issue 41 https://doi.org/10.1523/JNEUROSCI.2362-09.2009	journal	October 2009
Aβ43‐producing PS1 FAD mutants cause altered substrate interactions and respond to γ‐secretase modulation Trambauer, Johannes; Rodríguez Sarmiento, Rosa María; Fukumori, Akio EMBO reports, Vol. 21, Issue 1 https://doi.org/10.15252/embr.201947996	journal	November 2019
Generation and deposition of Aβ43 by the virtually inactive presenilin‐1 L435F mutant contradicts the presenilin loss‐of‐function hypothesis of Alzheimer's disease Kretner, Benedikt; Trambauer, Johannes; Fukumori, Akio EMBO Molecular Medicine, Vol. 8, Issue 5 https://doi.org/10.15252/emmm.201505952	journal	March 2016
The amyloid hypothesis of Alzheimer's disease at 25 years Selkoe, Dennis J.; Hardy, John EMBO Molecular Medicine, Vol. 8, Issue 6 https://doi.org/10.15252/emmm.201606210	journal	March 2016
γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding Hitzenberger, Manuel; Zacharias, Martin Frontiers in Chemistry, Vol. 6 https://doi.org/10.3389/fchem.2018.00640	journal	January 2019
Sampling the conformational space of the catalytic subunit of human γ-secretase Bai, Xiao-chen; Rajendra, Eeson; Yang, Guanghui eLife, Vol. 4 https://doi.org/10.7554/eLife.11182	journal	December 2015
The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase Bolduc, David M.; Montagna, Daniel R.; Seghers, Matthew C. eLife, Vol. 5 https://doi.org/10.7554/eLife.17578	journal	August 2016

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