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- PDB-7rlt: Structure of ligand-free ALDH1L1 (10-formyltetrahydrofolate dehyd... -

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Basic information

Entry
Database: PDB / ID: 7rlt
TitleStructure of ligand-free ALDH1L1 (10-formyltetrahydrofolate dehydrogenase)
ComponentsCytosolic 10-formyltetrahydrofolate dehydrogenase
KeywordsCYTOSOLIC PROTEIN / folate metabolism / acyl carrier protein / peptidyl carrier protein
Function / homology
Function and homology information


Metabolism of folate and pterines / aldehyde dehydrogenase (NADP+) activity / formyltetrahydrofolate dehydrogenase / formyltetrahydrofolate dehydrogenase activity / 10-formyltetrahydrofolate catabolic process / aldehyde dehydrogenase [NAD(P)+] activity / NADPH regeneration / aldehyde dehydrogenase (NAD+) activity / bile acid signaling pathway / folic acid metabolic process ...Metabolism of folate and pterines / aldehyde dehydrogenase (NADP+) activity / formyltetrahydrofolate dehydrogenase / formyltetrahydrofolate dehydrogenase activity / 10-formyltetrahydrofolate catabolic process / aldehyde dehydrogenase [NAD(P)+] activity / NADPH regeneration / aldehyde dehydrogenase (NAD+) activity / bile acid signaling pathway / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / protein-containing complex binding / protein-containing complex / cytosol
Similarity search - Function
10-formyltetrahydrofolate dehydrogenase / Formyl transferase, C-terminal domain superfamily / Formyl transferase, C-terminal / Formyl transferase, C-terminal domain / Formyl transferase-like, C-terminal domain superfamily / Phosphoribosylglycinamide formyltransferase, active site / Phosphoribosylglycinamide formyltransferase active site. / Formyl transferase, N-terminal / Formyl transferase / Formyl transferase, N-terminal domain superfamily ...10-formyltetrahydrofolate dehydrogenase / Formyl transferase, C-terminal domain superfamily / Formyl transferase, C-terminal / Formyl transferase, C-terminal domain / Formyl transferase-like, C-terminal domain superfamily / Phosphoribosylglycinamide formyltransferase, active site / Phosphoribosylglycinamide formyltransferase active site. / Formyl transferase, N-terminal / Formyl transferase / Formyl transferase, N-terminal domain superfamily / Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, cysteine active site / Aldehyde dehydrogenases cysteine active site. / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, N-terminal / Aldehyde dehydrogenase, C-terminal / Aldehyde/histidinol dehydrogenase / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain
Similarity search - Domain/homology
4'-PHOSPHOPANTETHEINE / Cytosolic 10-formyltetrahydrofolate dehydrogenase
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsTsybovsky, Y. / Sereda, V. / Golczak, M. / Krupenko, N.I. / Krupenko, S.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK54388 United States
CitationJournal: Commun Biol / Year: 2022
Title: Structure of putative tumor suppressor ALDH1L1.
Authors: Yaroslav Tsybovsky / Valentin Sereda / Marcin Golczak / Natalia I Krupenko / Sergey A Krupenko /
Abstract: Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP-dependent conversion of 10-formyltetrahydrofolate to ...Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain interactions. The C-terminal aldehyde dehydrogenase domains, which convert formyl to CO, form unusually large interfaces with the intermediate domains, homologs of acyl/peptidyl carrier proteins (A/PCPs), which transfer the formyl group between the catalytic domains. The 4'-phosphopantetheine arm of the intermediate domain is fully extended and reaches deep into the catalytic pocket of the C-terminal domain. Remarkably, the tetrameric state of ALDH1L1 is indispensable for catalysis because the intermediate domain transfers formyl between the catalytic domains of different protomers. These findings emphasize the versatility of A/PCPs in complex, highly dynamic enzymatic systems.
History
DepositionJul 26, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Cytosolic 10-formyltetrahydrofolate dehydrogenase
C: Cytosolic 10-formyltetrahydrofolate dehydrogenase
B: Cytosolic 10-formyltetrahydrofolate dehydrogenase
D: Cytosolic 10-formyltetrahydrofolate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)397,3748
Polymers395,9404
Non-polymers1,4334
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area30040 Å2
ΔGint-136 kcal/mol
Surface area72690 Å2

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Components

#1: Protein
Cytosolic 10-formyltetrahydrofolate dehydrogenase / 10-FTHFDH / FDH / Aldehyde dehydrogenase family 1 member L1 / FBP-CI


Mass: 98985.055 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Aldh1l1, Fthfd / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P28037, formyltetrahydrofolate dehydrogenase
#2: Chemical
ChemComp-PNS / 4'-PHOSPHOPANTETHEINE / Phosphopantetheine


Mass: 358.348 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H23N2O7PS / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: ligand-free ALDH1L1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.395 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 40 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0222 / Classification: refinement
EM software
IDNameVersionCategory
7Cootmodel fitting
11RELION3classification
12RELION33D reconstruction
13REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: D2 (2x2 fold dihedral)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 86276 / Symmetry type: POINT
Atomic model buildingProtocol: BACKBONE TRACE
Atomic model buildingPDB-ID: 2O2P

2o2p

RefinementCor.coef. Fo:Fc: 0.798 / Highest resolution: 3.7 Å / SU B: 36.781 / SU ML: 0.463
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.32156 --
obs0.32156 53619 100 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 88.446 Å2
Baniso -1Baniso -2Baniso -3
1-2.87 Å2-0.01 Å2-0.04 Å2
2---0.65 Å20.02 Å2
3----2.22 Å2
Refinement stepCycle: 1 / Total: 17996
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.01418328
ELECTRON MICROSCOPYr_bond_other_d0.0010.01716944
ELECTRON MICROSCOPYr_angle_refined_deg0.8771.65624800
ELECTRON MICROSCOPYr_angle_other_deg0.6241.64139604
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.5452316
ELECTRON MICROSCOPYr_dihedral_angle_2_deg31.96623.139892
ELECTRON MICROSCOPYr_dihedral_angle_3_deg13.403153168
ELECTRON MICROSCOPYr_dihedral_angle_4_deg13.1241596
ELECTRON MICROSCOPYr_chiral_restr0.0360.22400
ELECTRON MICROSCOPYr_gen_planes_refined0.0030.0220592
ELECTRON MICROSCOPYr_gen_planes_other0.0020.023336
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it1.6029.0679288
ELECTRON MICROSCOPYr_mcbond_other1.6029.0689287
ELECTRON MICROSCOPYr_mcangle_it2.96513.59911596
ELECTRON MICROSCOPYr_mcangle_other2.96513.59911597
ELECTRON MICROSCOPYr_scbond_it1.1539.1639040
ELECTRON MICROSCOPYr_scbond_other1.1539.1639037
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other2.26213.67413202
ELECTRON MICROSCOPYr_long_range_B_refined5.56719645
ELECTRON MICROSCOPYr_long_range_B_other5.56719646
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.7→3.796 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.49 3997 -
obs--100 %

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