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- EMDB-18973: Cryo-EM structure of Human SHMT1 -

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Basic information

Entry
Database: EMDB / ID: EMD-18973
TitleCryo-EM structure of Human SHMT1
Map dataCryo-EM structure of SHMT1.
Sample
  • Complex: human SHMT1
    • Protein or peptide: Serine hydroxymethyltransferase, cytosolic
    • Protein or peptide: Serine hydroxymethyltransferase, cytosolic
KeywordsRiboregulation / Serine / Glycine Metabolism / 1 carbon metablism / Moonlighting protein / RNA BINDING PROTEIN / TRANSFERASE
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsSpizzichino S / Marabelli C / Bharadwaj A / Jakobi AJ / Chaves-Sanjuan A / Giardina G / Bolognesi M / Cutruzzola F
Funding support Italy, 2 items
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, 2023-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18973.png

Downloads & links

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Map

FileDownload / File: emd_18973.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of SHMT1.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 400 pix.
= 355.6 Å		0.89 Å/pix.
x 400 pix.
= 355.6 Å		0.89 Å/pix.
x 400 pix.
= 355.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.889 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.045401618 - 0.6136779
Average (Standard dev.)0.00082313444 (±0.013248599)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 355.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of SHMT1. Half map 2

Fileemd_18973_half_map_1.map
AnnotationCryo-EM structure of SHMT1. Half map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of SHMT1. Half map 1

Fileemd_18973_half_map_2.map
AnnotationCryo-EM structure of SHMT1. Half map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human SHMT1

EntireName: human SHMT1
Components
  • Complex: human SHMT1
    • Protein or peptide: Serine hydroxymethyltransferase, cytosolic
    • Protein or peptide: Serine hydroxymethyltransferase, cytosolic

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Supramolecule #1: human SHMT1

SupramoleculeName: human SHMT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: SHMT1= homotetramer of 53kDa subunits
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 210 KDa

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Macromolecule #1: Serine hydroxymethyltransferase, cytosolic

MacromoleculeName: Serine hydroxymethyltransferase, cytosolic / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: glycine hydroxymethyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.662914 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: GSHMTMPVNG AHKDADLWSS HDKMLAQPLK DSDVEVYNII KKESNRQRVG LELIASENFA SRAVLEALGS CLNNKYSEGY PGQRYYGGT EFIDELETLC QKRALQAYKL DPQCWGVNVQ PYSGSPANFA VYTALVEPHG RIMGLDLPDG GHLTHGFMTD K KKISATSI ...String:
GSHMTMPVNG AHKDADLWSS HDKMLAQPLK DSDVEVYNII KKESNRQRVG LELIASENFA SRAVLEALGS CLNNKYSEGY PGQRYYGGT EFIDELETLC QKRALQAYKL DPQCWGVNVQ PYSGSPANFA VYTALVEPHG RIMGLDLPDG GHLTHGFMTD K KKISATSI FFESMPYKVN PDTGYINYDQ LEENARLFHP KLIIAGTSCY SRNLEYARLR KIADENGAYL MADMAHISGL VA AGVVPSP FEHCHVVTTT TH(LLP)TLRGCRA GMIFYRKGVK SVDPKTGKEI LYNLESLINS AVFPGLQGGP HNHAIAGVA VALKQAMTLE FKVYQHQVVA NCRALSEALT ELGYKIVTGG SDNHLILVDL RSKGTDGGRA EKVLEACSIA CNKNTCPGDR SALRPSGLR LGTPALTSRG LLEKDFQKVA HFIHRGIELT LQIQSDTGVR ATLKEFKERL AGDKYQAAVQ ALREEVESFA S LFPLPGLP DF

UniProtKB: Serine hydroxymethyltransferase, cytosolic

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Macromolecule #2: Serine hydroxymethyltransferase, cytosolic

MacromoleculeName: Serine hydroxymethyltransferase, cytosolic / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.434797 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: GSHMTMPVNG AHKDADLWSS HDKMLAQPLK DSDVEVYNII KKESNRQRVG LELIASENFA SRAVLEALGS CLNNKYSEGY PGQRYYGGT EFIDELETLC QKRALQAYKL DPQCWGVNVQ PYSGSPANFA VYTALVEPHG RIMGLDLPDG GHLTHGFMTD K KKISATSI ...String:
GSHMTMPVNG AHKDADLWSS HDKMLAQPLK DSDVEVYNII KKESNRQRVG LELIASENFA SRAVLEALGS CLNNKYSEGY PGQRYYGGT EFIDELETLC QKRALQAYKL DPQCWGVNVQ PYSGSPANFA VYTALVEPHG RIMGLDLPDG GHLTHGFMTD K KKISATSI FFESMPYKVN PDTGYINYDQ LEENARLFHP KLIIAGTSCY SRNLEYARLR KIADENGAYL MADMAHISGL VA AGVVPSP FEHCHVVTTT THKTLRGCRA GMIFYRKGVK SVDPKTGKEI LYNLESLINS AVFPGLQGGP HNHAIAGVAV ALK QAMTLE FKVYQHQVVA NCRALSEALT ELGYKIVTGG SDNHLILVDL RSKGTDGGRA EKVLEACSIA CNKNTCPGDR SALR PSGLR LGTPALTSRG LLEKDFQKVA HFIHRGIELT LQIQSDTGVR ATLKEFKERL AGDKYQAAVQ ALREEVESFA SLFPL PGLP DF

UniProtKB: Serine hydroxymethyltransferase, cytosolic

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.3 mg/mL
BufferpH: 7.2
Component:
ConcentrationFormulaName
150.0 mMNaClSodium Chloride
20.0 mMC8H18N2O4SHepes
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: blotted for 4 seconds before plunging.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 5450 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 120000
Sample stageSpecimen holder model: OTHER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4900000
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6fl5

Final reconstructionNumber classes used: 3 / Resolution.type: BY AUTHOR / Resolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 94430
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 2 / Software - Name: RELION (ver. 3.1)

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Atomic model buiding 1

Initial modelPDB ID:

1bj4


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 132
Output model

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

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