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- PDB-4uis: The cryoEM structure of human gamma-Secretase complex -

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Basic information

Entry
Database: PDB / ID: 4uis
TitleThe cryoEM structure of human gamma-Secretase complex
Components
  • (GAMMA-SECRETASE) x 4
  • LYSOZYME
KeywordsHYDROLASE / GAMMA-SECRETASE
Function / homology
Function and homology information


gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / Notch receptor processing / skin morphogenesis / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus / ciliary rootlet ...gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / Notch receptor processing / skin morphogenesis / membrane protein intracellular domain proteolysis / NOTCH4 Activation and Transmission of Signal to the Nucleus / ciliary rootlet / neural retina development / Regulated proteolysis of p75NTR / mitochondria-associated endoplasmic reticulum membrane contact site / aggresome / endoplasmic reticulum calcium ion homeostasis / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / astrocyte activation involved in immune response / regulation of postsynapse organization / Notch signaling pathway / regulation of neuron projection development / regulation of canonical Wnt signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / growth factor receptor binding / azurophil granule membrane / positive regulation of amyloid fibril formation / amyloid precursor protein catabolic process / positive regulation of dendritic spine development / amyloid-beta formation / membrane protein ectodomain proteolysis / positive regulation of receptor recycling / smooth endoplasmic reticulum / nuclear outer membrane / EPH-ephrin mediated repulsion of cells / cerebellum development / calcium ion homeostasis / Nuclear signaling by ERBB4 / viral release from host cell by cytolysis / endopeptidase activator activity / Degradation of the extracellular matrix / peptidoglycan catabolic process / negative regulation of ubiquitin-dependent protein catabolic process / neuron projection maintenance / rough endoplasmic reticulum / astrocyte activation / positive regulation of glycolytic process / NOTCH2 Activation and Transmission of Signal to the Nucleus / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / neuromuscular junction / PDZ domain binding / cell-cell adhesion / NOTCH3 Activation and Transmission of Signal to the Nucleus / protein processing / memory / sarcolemma / synapse organization / beta-catenin binding / kinetochore / cellular response to amyloid-beta / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / regulation of gene expression / cell wall macromolecule catabolic process / calcium channel activity / lysozyme / lysozyme activity / positive regulation of tumor necrosis factor production / melanosome / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / synaptic vesicle / nuclear membrane / ATPase binding / growth cone / early endosome membrane / endopeptidase activity / presynaptic membrane / cell cortex / aspartic-type endopeptidase activity / molecular adaptor activity / early endosome / defense response to bacterium / learning or memory / neuron projection / postsynapse / protein-macromolecule adaptor activity / intracellular signal transduction / mitochondrial inner membrane / apoptotic process / endosome membrane / cadherin binding / membrane raft / Amyloid fiber formation / negative regulation of gene expression / Golgi membrane / focal adhesion / lysosomal membrane / centrosome
Similarity search - Function
Peptidase A22A, presenilin 1 / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe / Nicastrin large lobe / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family ...Peptidase A22A, presenilin 1 / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe / Nicastrin large lobe / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Lysozyme-like domain superfamily
Similarity search - Domain/homology
Endolysin / Endolysin / Presenilin-1 / Nicastrin
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsSun, L. / Zhao, L. / Yang, G. / Yan, C. / Zhou, R. / Zhou, X. / Xie, T. / Zhao, Y. / Wu, S. / Li, X. / Shi, Y.
CitationJournal: Proc Natl Acad Sci U S A / Year: 2015
Title: Structural basis of human γ-secretase assembly.
Authors: Linfeng Sun / Lingyun Zhao / Guanghui Yang / Chuangye Yan / Rui Zhou / Xiaoyuan Zhou / Tian Xie / Yanyu Zhao / Shenjie Wu / Xueming Li / Yigong Shi /
Abstract: The four-component intramembrane protease γ-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of γ- ...The four-component intramembrane protease γ-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of γ-secretase remain to be specifically assigned. Here we report a 3D structure of human γ-secretase at 4.32-Å resolution, determined by single-particle, electron cryomicroscopy in the presence of digitonin and with a T4 lysozyme fused to the amino terminus of presenilin 1 (PS1). The overall structure of this human γ-secretase is very similar to that of wild-type γ-secretase determined in the presence of amphipols. The 20 TMs are unambiguously assigned to the four components, revealing principles of subunit assembly. Within the transmembrane region, PS1 is centrally located, with its amino-terminal fragment (NTF) packing against Pen-2 and its carboxyl-terminal fragment (CTF) interacting with Aph-1. The only TM of nicastrin associates with Aph-1 at the thick end of the TM horseshoe, and the extracellular domain of nicastrin directly binds Pen-2 at the thin end. TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of γ-secretase.
History
DepositionApr 3, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2017Group: Data collection / Category: em_software
Item: _em_software.fitting_id / _em_software.image_processing_id / _em_software.name
Revision 1.2Nov 13, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature / pdbx_validate_polymer_linkage
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _pdbx_validate_polymer_linkage.dist / _pdbx_validate_polymer_linkage.label_alt_id_1 / _pdbx_validate_polymer_linkage.label_alt_id_2

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Structure visualization

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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
  • EMDB-2974
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Structure viewerMolecule:
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Assembly

Deposited unit
A: GAMMA-SECRETASE
B: GAMMA-SECRETASE
C: GAMMA-SECRETASE
D: GAMMA-SECRETASE
G: LYSOZYME


Theoretical massNumber of molelcules
Total (without water)127,3085
Polymers127,3085
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

#1: Protein GAMMA-SECRETASE


Mass: 63331.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human) / References: UniProt: Q92542*PLUS
#2: Protein GAMMA-SECRETASE


Mass: 23547.639 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human) / References: UniProt: P49768*PLUS
#3: Protein GAMMA-SECRETASE


Mass: 16698.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human)
#4: Protein GAMMA-SECRETASE


Mass: 5294.518 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human)
#5: Protein LYSOZYME


Mass: 18435.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human)
References: UniProt: A0A097J809, UniProt: D9IEF7*PLUS, lysozyme
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: T4-LYSOZYME FUSION GAMMA- SECRETASE / Type: COMPLEX
Buffer solutionName: 0.1% DIGITONIN, 25 MM HEPES, PH 7.4, AND 150 MM NACL. / pH: 7.4
Details: 0.1% DIGITONIN, 25 MM HEPES, PH 7.4, AND 150 MM NACL.
SpecimenConc.: 4.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: HOLEY CARBON
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
Details: VITRIFICATION 1 -- CRYOGEN- ETHANE, HUMIDITY- 100, TEMPERATURE- 277, INSTRUMENT- FEI VITROBOT MARK IV, METHOD- BLOT FOR 3 SECONDS BEFORE PLUNGING,

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Date: Dec 22, 2014
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Cs: 1.4 mm
Image recordingElectron dose: 4.5 e/Å2 / Film or detector model: DIRECT ELECTRON DE-12 (4k x 3k)
Image scansNum. digital images: 2000

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Processing

EM software
IDNameCategory
1UCSF Chimeramodel fitting
2RELION3D reconstruction
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.4 Å / Num. of particles: 177207 / Nominal pixel size: 1.32 Å / Actual pixel size: 1.32 Å
Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-2974. (DEPOSITION ID: 13293
Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL / Details: METHOD--FLEXIBLE
Atomic model buildingPDB-ID: 4R12

4r12


Accession code: 4R12 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 4.4 Å
Refinement stepCycle: LAST / Highest resolution: 4.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8461 0 0 0 8461

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