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- PDB-8r7h: Cryo-EM structure of Human SHMT1 -

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Basic information

Entry
Database: PDB / ID: 8r7h
TitleCryo-EM structure of Human SHMT1
Components(Serine hydroxymethyltransferase, cytosolic) x 2
KeywordsTRANSFERASE / Riboregulation / Serine / Glycine Metabolism / 1 carbon metablism / Moonlighting protein / RNA BINDING PROTEIN
Function / homology
Function and homology information


cellular response to tetrahydrofolate / Carnitine synthesis / purine nucleobase biosynthetic process / L-serine metabolic process / glycine metabolic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / serine binding / Metabolism of folate and pterines ...cellular response to tetrahydrofolate / Carnitine synthesis / purine nucleobase biosynthetic process / L-serine metabolic process / glycine metabolic process / glycine hydroxymethyltransferase / glycine hydroxymethyltransferase activity / glycine biosynthetic process from serine / serine binding / Metabolism of folate and pterines / L-serine catabolic process / tetrahydrofolate metabolic process / tetrahydrofolate interconversion / dTMP biosynthetic process / cobalt ion binding / folic acid metabolic process / small molecule binding / mRNA regulatory element binding translation repressor activity / cellular response to leukemia inhibitory factor / mRNA 5'-UTR binding / pyridoxal phosphate binding / protein homotetramerization / negative regulation of translation / protein homodimerization activity / mitochondrion / zinc ion binding / extracellular exosome / nucleoplasm / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Serine hydroxymethyltransferase, pyridoxal phosphate binding site / Serine hydroxymethyltransferase pyridoxal-phosphate attachment site. / Serine hydroxymethyltransferase / Serine hydroxymethyltransferase-like domain / Serine hydroxymethyltransferase / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Serine hydroxymethyltransferase, cytosolic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsSpizzichino, S. / Marabelli, C. / Bharadwaj, A. / Jakobi, A.J. / Chaves-Sanjuan, A. / Giardina, G. / Bolognesi, M. / Cutruzzola, F.
Funding support Italy, 2items
OrganizationGrant numberCountry
Italian Association for Cancer ResearchAIRC IG-23125 Italy
Other private
CitationJournal: Mol Cell / Year: 2024
Title: Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1.
Authors: Sharon Spizzichino / Federica Di Fonzo / Chiara Marabelli / Angela Tramonti / Antonio Chaves-Sanjuan / Alessia Parroni / Giovanna Boumis / Francesca Romana Liberati / Alessio Paone / Linda ...Authors: Sharon Spizzichino / Federica Di Fonzo / Chiara Marabelli / Angela Tramonti / Antonio Chaves-Sanjuan / Alessia Parroni / Giovanna Boumis / Francesca Romana Liberati / Alessio Paone / Linda Celeste Montemiglio / Matteo Ardini / Arjen J Jakobi / Alok Bharadwaj / Paolo Swuec / Gian Gaetano Tartaglia / Alessandro Paiardini / Roberto Contestabile / Antonello Mai / Dante Rotili / Francesco Fiorentino / Alberto Macone / Alessandra Giorgi / Giancarlo Tria / Serena Rinaldo / Martino Bolognesi / Giorgio Giardina / Francesca Cutruzzolà /
Abstract: RNA can directly control protein activity in a process called riboregulation; only a few mechanisms of riboregulation have been described in detail, none of which have been characterized on ...RNA can directly control protein activity in a process called riboregulation; only a few mechanisms of riboregulation have been described in detail, none of which have been characterized on structural grounds. Here, we present a comprehensive structural, functional, and phylogenetic analysis of riboregulation of cytosolic serine hydroxymethyltransferase (SHMT1), the enzyme interconverting serine and glycine in one-carbon metabolism. We have determined the cryoelectron microscopy (cryo-EM) structure of human SHMT1 in its free- and RNA-bound states, and we show that the RNA modulator competes with polyglutamylated folates and acts as an allosteric switch, selectively altering the enzyme's reactivity vs. serine. In addition, we identify the tetrameric assembly and a flap structural motif as key structural elements necessary for binding of RNA to eukaryotic SHMT1. The results presented here suggest that riboregulation may have played a role in evolution of eukaryotic SHMT1 and in compartmentalization of one-carbon metabolism. Our findings provide insights for RNA-based therapeutic strategies targeting this cancer-linked metabolic pathway.
History
DepositionNov 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine hydroxymethyltransferase, cytosolic
B: Serine hydroxymethyltransferase, cytosolic
C: Serine hydroxymethyltransferase, cytosolic
D: Serine hydroxymethyltransferase, cytosolic


Theoretical massNumber of molelcules
Total (without water)214,1954
Polymers214,1954
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area19030 Å2
ΔGint-101 kcal/mol
Surface area72430 Å2
MethodPISA

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Components

#1: Protein Serine hydroxymethyltransferase, cytosolic / SHMT / Glycine hydroxymethyltransferase / Serine methylase


Mass: 53662.914 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHMT1 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P34896, glycine hydroxymethyltransferase
#2: Protein Serine hydroxymethyltransferase, cytosolic


Mass: 53434.797 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHMT1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P34896
Has ligand of interestN

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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: human SHMT1 / Type: COMPLEX / Details: SHMT1= homotetramer of 53kDa subunits / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.21 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21 (bacteria)
Buffer solutionpH: 7.2
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaCl1
220 mMHepesC8H18N2O4S1
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: blotted for 4 seconds before plunging

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 120000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN / Specimen holder model: OTHER
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5450

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Processing

EM software
IDNameVersionCategory
1RELION3.1particle selection
2EPU2.8image acquisition
4CTFFIND4CTF correction
7UCSF Chimeramodel fitting
8Coot0.9.6model fitting
10PHENIX1-17-1-3660model refinement
11RELION3.1initial Euler assignment
12RELION3.1final Euler assignment
13RELION3.1classification
14RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4900000
3D reconstructionResolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 94430 / Num. of class averages: 3 / Symmetry type: POINT
Atomic model buildingB value: 132 / Protocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 1BJ4

1bj4


Pdb chain-ID: A / Accession code: 1BJ4 / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00214542
ELECTRON MICROSCOPYf_angle_d0.40619676
ELECTRON MICROSCOPYf_dihedral_angle_d3.6032032
ELECTRON MICROSCOPYf_chiral_restr0.0362190
ELECTRON MICROSCOPYf_plane_restr0.0032566

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