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- PDB-2lp1: The solution NMR structure of the transmembrane C-terminal domain... -

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Basic information

Entry
Database: PDB / ID: 2lp1
TitleThe solution NMR structure of the transmembrane C-terminal domain of the amyloid precursor protein (C99)
ComponentsC99
KeywordsMEMBRANE PROTEIN / AMYLOID PRECURSOR PROTEIN C-TERMINAL FRAGMENT / ALZHEIMER'S DISEASE / AMYLOID-BETA PRECURSOR / TRANSMEMBRANE PROTEIN
Function / homology
Function and homology information


cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / NMDA selective glutamate receptor signaling pathway / microglia development / regulation of Wnt signaling pathway / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity ...cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / NMDA selective glutamate receptor signaling pathway / microglia development / regulation of Wnt signaling pathway / regulation of synapse structure or activity / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / Golgi-associated vesicle / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / COPII-coated ER to Golgi transport vesicle / suckling behavior / nuclear envelope lumen / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / The NLRP3 inflammasome / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / negative regulation of long-term synaptic potentiation / regulation of presynapse assembly / transition metal ion binding / regulation of multicellular organism growth / negative regulation of neuron differentiation / intracellular copper ion homeostasis / ECM proteoglycans / positive regulation of T cell migration / spindle midzone / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / protein serine/threonine kinase binding / regulation of peptidyl-tyrosine phosphorylation / clathrin-coated pit / positive regulation of chemokine production / forebrain development / Notch signaling pathway / neuron projection maintenance / Mitochondrial protein degradation / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / cholesterol metabolic process / positive regulation of calcium-mediated signaling / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / response to interleukin-1 / extracellular matrix organization / positive regulation of mitotic cell cycle / axonogenesis / adult locomotory behavior / platelet alpha granule lumen / trans-Golgi network membrane / learning / positive regulation of interleukin-1 beta production / dendritic shaft / positive regulation of peptidyl-threonine phosphorylation / positive regulation of long-term synaptic potentiation / central nervous system development / endosome lumen / locomotory behavior / astrocyte activation / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / synapse organization / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / serine-type endopeptidase inhibitor activity / neuromuscular junction / visual learning / recycling endosome / cognition / Golgi lumen / positive regulation of inflammatory response / positive regulation of interleukin-6 production / neuron cellular homeostasis / positive regulation of non-canonical NF-kappaB signal transduction / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / endocytosis / cellular response to amyloid-beta / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle / Platelet degranulation / apical part of cell
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics, simulated annealing
Model detailsclosest to the average, model 5
AuthorsBarrett, P.J. / Song, Y. / Van Horn, W.D. / Hustedt, E.J. / Schafer, J.M. / Hadziselimovic, A. / Beel, A.J. / Sanders, C.R.
CitationJournal: Science / Year: 2012
Title: The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.
Authors: Barrett, P.J. / Song, Y. / Van Horn, W.D. / Hustedt, E.J. / Schafer, J.M. / Hadziselimovic, A. / Beel, A.J. / Sanders, C.R.
History
DepositionJan 30, 2012Deposition site: BMRB / Processing site: RCSB
Revision 1.0Jun 6, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 20, 2012Group: Database references
Revision 1.2May 1, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_nmr_software / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_nmr_software.name / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: C99


Theoretical massNumber of molelcules
Total (without water)13,8021
Polymers13,8021
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)30 / 100structures with the lowest energy
RepresentativeModel #1closest to the average

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Components

#1: Protein C99 / Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Cerebral vascular ...Amyloid beta A4 protein / ABPP / APPI / APP / Alzheimer disease amyloid protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 13801.766 Da / Num. of mol.: 1 / Fragment: UNP residues 683-728
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: A4, AD1, APP / Production host: Escherichia coli (E. coli) / References: UniProt: P05067

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDType
1112D 1H-15N HSQC-TROSY
1213D HNCA
1313D HN(CA)CB
1413D HN(CO)CA
1513D HN(COCA)CB
1613D HNCO
1713D gnoesyNhsqc
NMR detailsText: All 2D and 3D experiments were TROSY based. For the RDC data collection, the TROSY/Semi-TROSY method was used.

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Sample preparation

DetailsContents: 10 % lyso myristoyl phosphatidylglycerol, 10 % [U-2H] D2O, 100 mM imidazole, 250 uM [U-100% 15N] APP_C99, 1 mM EDTA, 90% H2O/10% D2O
Solvent system: 90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
10 %lyso myristoyl phosphatidylglycerol-11
10 %D2O-2[U-2H]1
100 mMimidazole-31
250 uMAPP_C99-4[U-100% 15N]1
1 mMEDTA-51
10 %lyso myristoyl phosphatidylglycerol-62
10 %D2O-7[U-2H]2
100 mMimidazole-82
250 uMAPP_C99-9[U-100% 15N]2
1 mMEDTA-102
10 %lyso myristoyl phosphatidylglycerol-113
10 %D2O-12[U-2H]3
100 mMimidazole-133
250 uMAPP_C99-14[U-100% 15N]3
1 mMEDTA-153
10 %lyso myristoyl phosphatidylglycerol-164
10 %D2O-17[U-2H]4
100 mMimidazole-184
250 uMAPP_C99-19[U-100% 15N]4
1 mMEDTA-204
10 %lyso myristoyl phosphatidylglycerol-215
10 %D2O-22[U-2H]5
100 mMimidazole-235
250 uMAPP_C99-24[U-15N; U-2H]5
7 %Acrylamide-255
0.5 %AMPS-265
1 mMEDTA-275
9 %lyso myristoyl phosphatidylglycerol-286
1 mMAPP_C99-29[U-100% 13C; U-100% 15N; U-80% 2H]6
10 %D2O-30[U-2H]6
2.5 mMEDTA-316
250 mMimidazole-326
Sample conditionspH: 6.5 / Pressure: ambient / Temperature: 318 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AMXBrukerAMX8001
Bruker AMXBrukerAMX6002
Varian INOVAVarianINOVA9003

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Processing

NMR software
NameVersionDeveloperClassification
X-PLOR NIH2.24Schwieters, Kuszewski, Tjandra and Clorestructure solution
X-PLOR NIH2.24Schwieters, Kuszewski, Tjandra and Clorerefinement
NMRDrawLinux9Delaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxdata analysis
Sparky3.114Goddarddata analysis
Sparky3.114Goddardchemical shift assignment
Sparky3.114Goddardpeak picking
NMRPipeLinux9Delaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
TALOSLinux9Cornilescu, Delaglio and Baxgeometry optimization
TALOSLinux9Cornilescu, Delaglio and Baxstructure solution
ProcheckNMR3.5.4Laskowski and MacArthurdata analysis
ProcheckNMR3.5.4Laskowski and MacArthurstructure solution
TopSpin3Bruker Biospincollection
RefinementMethod: molecular dynamics, simulated annealing / Software ordinal: 1
Details: RESTRAINED MOLECULAR DYNAMICS WITH SIMULATED ANNEALING, FOLLOWED BY POWELL ENERGY MINIMIZATION
NMR constraintsNOE constraints total: 65 / NOE intraresidue total count: 0 / NOE long range total count: 0 / NOE medium range total count: 22 / NOE sequential total count: 43 / Hydrogen bond constraints total count: 13 / Protein chi angle constraints total count: 0 / Protein other angle constraints total count: 0 / Protein phi angle constraints total count: 33 / Protein psi angle constraints total count: 32
NMR representativeSelection criteria: closest to the average
NMR ensembleAverage torsion angle constraint violation: 0.351 °
Conformer selection criteria: structures with the lowest energy
Conformers calculated total number: 100 / Conformers submitted total number: 30 / Maximum lower distance constraint violation: 0 Å / Maximum torsion angle constraint violation: 0.56 ° / Maximum upper distance constraint violation: 0 Å / Torsion angle constraint violation method: NIH Xplor
NMR ensemble rmsDistance rms dev: 0 Å / Distance rms dev error: 0 Å

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