Sampling the conformational space of the catalytic subunit of human g-secretase

Xiao Chen Bai, Eeson Rajendra, Guanghui Yang, Yigong Shi, Sjors H.W. Scheres

Research output: Contribution to journalArticle

236 Citations (Scopus)

Abstract

Human g-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer’s disease. Our previous cryo-EM structure of g- secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to the known components of g-secretase. In addition, we present a g-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain.

Original languageEnglish (US)
Article numbere11182
JournaleLife
Volume4
Issue numberDecember2015
DOIs
StatePublished - Dec 1 2015

Fingerprint

Amyloid Precursor Protein Secretases
Catalytic Domain
Presenilins
Sampling
Conformations
Amyloid beta-Protein Precursor
Image classification
Substrates
Plasticity
Alzheimer Disease
Esters
Peptide Hydrolases
Membranes
Neoplasms

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Bai, X. C., Rajendra, E., Yang, G., Shi, Y., & Scheres, S. H. W. (2015). Sampling the conformational space of the catalytic subunit of human g-secretase. eLife, 4(December2015), [e11182]. https://doi.org/10.7554/eLife.11182

Sampling the conformational space of the catalytic subunit of human g-secretase. / Bai, Xiao Chen; Rajendra, Eeson; Yang, Guanghui; Shi, Yigong; Scheres, Sjors H.W.

In: eLife, Vol. 4, No. December2015, e11182, 01.12.2015.

Research output: Contribution to journalArticle

Bai, XC, Rajendra, E, Yang, G, Shi, Y & Scheres, SHW 2015, 'Sampling the conformational space of the catalytic subunit of human g-secretase', eLife, vol. 4, no. December2015, e11182. https://doi.org/10.7554/eLife.11182
Bai, Xiao Chen ; Rajendra, Eeson ; Yang, Guanghui ; Shi, Yigong ; Scheres, Sjors H.W. / Sampling the conformational space of the catalytic subunit of human g-secretase. In: eLife. 2015 ; Vol. 4, No. December2015.
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