5FN4

Cryo-EM structure of gamma secretase in class 2 of the apo- state ensemble

Summary for 5FN4

• Entry DOI: 10.2210/pdb5fn4/pdb
• Related: 5FN2 5FN3 5FN5
• EMDB information: 3239
• Descriptor: Nicastrin, Presenilin-1, Gamma-secretase subunit APH-1A, ... (5 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 174048.04

Authors

Bai, X.C.,Rajendra, E.,Yang, G.H.,Shi, Y.G.,Scheres, S.H.W. (deposition date: 2015-11-10, release date: 2015-12-16, Last modification date: 2024-10-23)

Primary citation

Bai, X.C.,Rajendra, E.,Yang, G.,Shi, Y.,Scheres, S.H.
Sampling the conformational space of the catalytic subunit of human gamma-secretase.
Elife, 4:-, 2015

PubMed Abstract: Human γ-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 γ-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 γ-secretase. In addition, we present a γ-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.

PubMed: 26623517
DOI: 10.7554/eLife.11182

Experimental method

ELECTRON MICROSCOPY (4 Å)