[English] 日本語
Yorodumi
- PDB-4uis: The cryoEM structure of human gamma-Secretase complex -

+
Open data


ID or keywords:

Loading...

-
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


Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / synaptic vesicle targeting / positive regulation of coagulation / negative regulation of axonogenesis / central nervous system myelination / membrane protein intracellular domain proteolysis / growth factor receptor binding / T cell activation involved in immune response / skin morphogenesis / choline transport / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / neural retina development / regulation of resting membrane potential / myeloid dendritic cell differentiation / L-glutamate import across plasma membrane / Regulated proteolysis of p75NTR / regulation of phosphorylation / locomotion / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / smooth endoplasmic reticulum calcium ion homeostasis / embryonic limb morphogenesis / regulation of postsynapse organization / astrocyte activation involved in immune response / cell fate specification / regulation of canonical Wnt signaling pathway / skeletal system morphogenesis / aggresome / myeloid cell homeostasis / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / ciliary rootlet / positive regulation of dendritic spine development / positive regulation of amyloid fibril formation / positive regulation of receptor recycling / regulation of neuron projection development / protein glycosylation / blood vessel development / mitochondrial transport / amyloid precursor protein catabolic process / adult behavior / heart looping / cerebral cortex cell migration / amyloid-beta formation / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / autophagosome assembly / EPH-ephrin mediated repulsion of cells / negative regulation of ubiquitin-dependent protein catabolic process / endopeptidase activator activity / neuron development / somitogenesis / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / viral release from host cell by cytolysis / calcium ion homeostasis / T cell proliferation / regulation of synaptic transmission, glutamatergic / rough endoplasmic reticulum / Notch signaling pathway / Degradation of the extracellular matrix / neuron projection maintenance / peptidoglycan catabolic process / NOTCH2 Activation and Transmission of Signal to the Nucleus / cerebellum development / cellular response to calcium ion / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / thymus development / positive regulation of glycolytic process / epithelial cell proliferation / post-embryonic development / PDZ domain binding / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / apoptotic signaling pathway / synapse organization / neuromuscular junction / sarcolemma
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

-
Structure visualization

Movie
  • Deposited structure unit
  • Imaged by Jmol
  • Download
  • Simplified surface model + fitted atomic model
  • EMDB-2974
  • Imaged by Jmol
  • Download
  • Superimposition on EM map
  • EMDB-2974
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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

-
Experimental details

-
Experiment

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

-
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,

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more