5A63

Cryo-EM structure of the human gamma-secretase complex at 3.4 angstrom resolution.


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.40 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

An Atomic Structure of Human Gamma-Secretase

Bai, X.Yan, C.Yang, G.Lu, P.Ma, D.Sun, L.Zhou, R.Scheres, S.H.W.Shi, Y.

(2015) Nature 525: 212

  • DOI: https://doi.org/10.1038/nature14892
  • Primary Citation of Related Structures:  
    5A63

  • PubMed Abstract: 

    Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.


  • Organizational Affiliation

    MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nicastrin709Homo sapiensMutation(s): 0 
Gene Names: NCSTNKIAA0253UNQ1874/PRO4317
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q92542 (Homo sapiens)
Explore Q92542 
Go to UniProtKB:  Q92542
PHAROS:  Q92542
GTEx:  ENSG00000162736 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92542
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Presenilin-1467Homo sapiensMutation(s): 0 
Gene Names: PSEN1AD3PS1PSNL1
EC: 3.4.23
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P49768 (Homo sapiens)
Explore P49768 
Go to UniProtKB:  P49768
PHAROS:  P49768
GTEx:  ENSG00000080815 
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UniProt GroupP49768
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Gamma-secretase subunit APH-1A265Homo sapiensMutation(s): 0 
Gene Names: APH1APSFCGI-78UNQ579/PRO1141
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q96BI3 (Homo sapiens)
Explore Q96BI3 
Go to UniProtKB:  Q96BI3
PHAROS:  Q96BI3
GTEx:  ENSG00000117362 
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UniProt GroupQ96BI3
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Gamma-secretase subunit PEN-2101Homo sapiensMutation(s): 0 
Gene Names: PSENENPEN2MDS033
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NZ42 (Homo sapiens)
Explore Q9NZ42 
Go to UniProtKB:  Q9NZ42
PHAROS:  Q9NZ42
GTEx:  ENSG00000205155 
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UniProt GroupQ9NZ42
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E, G, H, I, J
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 6
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G89225LT
GlyCosmos:  G89225LT
GlyGen:  G89225LT
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.40 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
RECONSTRUCTIONRELION

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-05
    Type: Initial release
  • Version 1.1: 2015-08-19
    Changes: Database references
  • Version 1.2: 2015-08-26
    Changes: Database references
  • Version 1.3: 2015-09-16
    Changes: Database references, Structure summary
  • Version 1.4: 2016-12-28
    Changes: Other
  • Version 1.5: 2017-08-02
    Changes: Data collection
  • Version 1.6: 2019-09-11
    Changes: Data collection, Database references, Derived calculations, Source and taxonomy, Structure summary
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary