Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Proceedings of the National Academy of Sciences of the United States of America
Shangyu DangYigong Shi

Abstract

Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of γ-secretase), making modulation of γ-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact γ-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to γ-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Aβ42, Aβ40, and Aβ38. The molar ratio of the cleavage products Aβ42 over Aβ40 by PSH is nearly identical to that by γ-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of γ-secretase also modulate PSH similarly in terms of the Aβ42/Aβ40 ratio. Structural analysis reveals association of a known γ-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of γ-secretase.

References

Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Sep 19, 2001·Journal of Neurology, Neurosurgery, and Psychiatry·N SodeyamaY Komatsuzaki
Oct 24, 2002·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsThomas C Terwilliger
Mar 20, 2003·The Journal of Biological Chemistry·Anna Y KornilovaMichael S Wolfe
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Oct 9, 2004·The Journal of Organic Chemistry·Jiong ChunYue-Ming Li
Jan 13, 2006·Journal of Neurochemistry·Mostafa BentahirBart De Strooper
Jul 25, 2007·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Antony E ShrimptonRichard L Davis
Oct 25, 2007·Cell·Dennis J Selkoe, Michael S Wolfe
Apr 23, 2009·Assay and Drug Development Technologies·Martina Bielefeld-Sevigny
Sep 5, 2009·The Journal of Biological Chemistry·Daniel R DriesGang Yu
Oct 12, 2010·PloS One·Celia Torres-AranciviaIban Ubarretxena-Belandia
Jul 5, 2011·Nature Neuroscience·Takashi SaitoTakaomi C Saido
Nov 30, 2011·Journal of Neurochemistry·Alison Goate, John Hardy
Jan 10, 2012·ACS Chemical Neuroscience·Christina J CrumpYue-Ming Li
Feb 9, 2012·Cold Spring Harbor Perspectives in Medicine·Bart De StrooperMichael S Wolfe
Mar 31, 2012·The Journal of Biological Chemistry·De-Ming ChauYue-Ming Li
Apr 17, 2012·The EMBO Journal·Lucía Chávez-GutiérrezBart De Strooper
Feb 12, 2013·The Journal of Biological Chemistry·Nikolay PozdnyakovDouglas S Johnson
Apr 19, 2013·Molecular Neurobiology·Jun Seo GooDae Youn Hwang
Apr 26, 2013·Biochemistry·Christina J CrumpYue-Ming Li
Jun 26, 2013·Biochimica Et Biophysica Acta·Todd E GoldeLucio Miele
Oct 9, 2013·Biochimica Et Biophysica Acta·Michael S Wolfe
Dec 18, 2013·The Journal of Biological Chemistry·Hermien AcxBart De Strooper
Jul 22, 2014·Nature·Peilong LuYigong Shi
Sep 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Tian XieYigong Shi

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Citations

Jan 27, 2016·Current Opinion in Structural Biology·Linfeng SunYigong Shi
Apr 29, 2015·Proceedings of the National Academy of Sciences of the United States of America·Linfeng SunYigong Shi
Jan 27, 2016·Proceedings of the National Academy of Sciences of the United States of America·Siniša Urban
Dec 25, 2015·Proceedings of the National Academy of Sciences of the United States of America·David M BolducMichael S Wolfe
Aug 19, 2015·Nature·Xiao-Chen BaiYigong Shi
Feb 1, 2018·The Journal of Biological Chemistry·Swe-Htet NaingRaquel L Lieberman
Feb 6, 2020·Chemical Communications : Chem Comm·Jing ZhaoChunyu Wang
Aug 28, 2020·Frontiers in Molecular Neuroscience·Jing ZhaoChunyu Wang
Dec 1, 2018·Emerging Topics in Life Sciences·Julie A Maupin-Furlow
Dec 19, 2018·Proceedings of the National Academy of Sciences of the United States of America·Shenjie WuYigong Shi
Feb 8, 2018·Biophysical Journal·Swe-Htet NaingRaquel L Lieberman
Apr 26, 2020·Seminars in Cell & Developmental Biology·Akio FukumoriHarald Steiner
Apr 12, 2018·Biophysical Journal·Mia C BrownIban Ubarretxena-Belandia
May 20, 2020·Seminars in Cell & Developmental Biology·Manuel HitzenbergerChristina Scharnagl
Jun 28, 2019·ACS Chemical Neuroscience·Manuel Hitzenberger, Martin Zacharias

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