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- EMDB-50182: cryo-EM structure of human LST2 bound to human mTOR complex 1, fo... -

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Basic information

Entry
Database: EMDB / ID: EMD-50182
Titlecryo-EM structure of human LST2 bound to human mTOR complex 1, focused on RAPTOR
Map data
Sample
  • Complex: mTORC1 in complex with LST2
    • Protein or peptide: Regulatory-associated protein of mTOR
    • Protein or peptide: Lateral signaling target protein 2 homolog
KeywordsMTOR / MTORC1 / LST2 / ZFYVE28 / EGFR / TOS / SIGNALING PROTEIN
Function / homology
Function and homology information


negative regulation of epidermal growth factor-activated receptor activity / positive regulation of pentose-phosphate shunt / TORC1 complex / TORC1 signaling / positive regulation of odontoblast differentiation / cellular response to L-leucine / Amino acids regulate mTORC1 / MTOR signalling / Energy dependent regulation of mTOR by LKB1-AMPK / phosphatidylinositol-3-phosphate binding ...negative regulation of epidermal growth factor-activated receptor activity / positive regulation of pentose-phosphate shunt / TORC1 complex / TORC1 signaling / positive regulation of odontoblast differentiation / cellular response to L-leucine / Amino acids regulate mTORC1 / MTOR signalling / Energy dependent regulation of mTOR by LKB1-AMPK / phosphatidylinositol-3-phosphate binding / positive regulation of osteoclast differentiation / cellular response to osmotic stress / protein serine/threonine kinase inhibitor activity / enzyme-substrate adaptor activity / positive regulation of transcription by RNA polymerase III / regulation of cell size / Macroautophagy / protein kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / mTORC1-mediated signalling / social behavior / HSF1-dependent transactivation / positive regulation of TOR signaling / TOR signaling / positive regulation of G1/S transition of mitotic cell cycle / cellular response to nutrient levels / positive regulation of lipid biosynthetic process / 14-3-3 protein binding / positive regulation of endothelial cell proliferation / cellular response to starvation / positive regulation of glycolytic process / negative regulation of autophagy / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / regulation of autophagy / regulation of cell growth / cellular response to amino acid stimulus / TP53 Regulates Metabolic Genes / cellular response to glucose stimulus / small GTPase binding / cytoplasmic stress granule / positive regulation of peptidyl-serine phosphorylation / protein-macromolecule adaptor activity / cellular response to hypoxia / early endosome membrane / positive regulation of cell growth / lysosome / response to xenobiotic stimulus / lysosomal membrane / neuronal cell body / DNA damage response / dendrite / protein-containing complex binding / protein kinase binding / nucleoplasm / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Lateral signaling target protein 2, FYVE domain / : / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / FYVE zinc finger / FYVE zinc finger / Protein present in Fab1, YOTB, Vac1, and EEA1 / Zinc finger, FYVE-related ...Lateral signaling target protein 2, FYVE domain / : / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / FYVE zinc finger / FYVE zinc finger / Protein present in Fab1, YOTB, Vac1, and EEA1 / Zinc finger, FYVE-related / Zinc finger FYVE/FYVE-related type profile. / HEAT repeat / HEAT repeat / Zinc finger, FYVE/PHD-type / Armadillo-like helical / Armadillo-type fold / Zinc finger, RING/FYVE/PHD-type / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Regulatory-associated protein of mTOR / Lateral signaling target protein 2 homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsCraigie LM / Maier T
Funding support Switzerland, European Union, 2 items
OrganizationGrant numberCountry
Swiss National Science Foundation179323 Switzerland
H2020 Marie Curie Actions of the European Commission812830European Union
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
Authors: Stefania Battaglioni / Louise-Marie Craigie / Sofia Filippini / Timm Maier / Michael N Hall /
Abstract: TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, ...TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.
History
DepositionApr 26, 2024-
Header (metadata) releaseAug 14, 2024-
Map releaseAug 14, 2024-
UpdateAug 28, 2024-
Current statusAug 28, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50182.png

Downloads & links

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Map

FileDownload / File: emd_50182.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.31 Å/pix.
x 512 pix.
= 670.72 Å		1.31 Å/pix.
x 512 pix.
= 670.72 Å		1.31 Å/pix.
x 512 pix.
= 670.72 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.31 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-2.5929286 - 3.2557654
Average (Standard dev.)0.00013283736 (±0.02694005)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 670.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50182_msk_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_50182_half_map_1.map
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Half map: #1

Fileemd_50182_half_map_2.map
Projections & Slices
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Sample components

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Entire : mTORC1 in complex with LST2

EntireName: mTORC1 in complex with LST2
Components
  • Complex: mTORC1 in complex with LST2
    • Protein or peptide: Regulatory-associated protein of mTOR
    • Protein or peptide: Lateral signaling target protein 2 homolog

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Supramolecule #1: mTORC1 in complex with LST2

SupramoleculeName: mTORC1 in complex with LST2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Regulatory-associated protein of mTOR

MacromoleculeName: Regulatory-associated protein of mTOR / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 152.764656 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHHHHH EQKLISEEDL DYKDDDDKME SEMLQSPLLG LGEEDEADLT DWNLPLAFMK KRHCEKIEGS KSLAQSWRMK DRMKTVSVA LVLCLNVGVD PPDVVKTTPC ARLECWIDPL SMGPQKALET IGANLQKQYE NWQPRARYKQ SLDPTVDEVK K LCTSLRRN ...String:
HHHHHHHHHH EQKLISEEDL DYKDDDDKME SEMLQSPLLG LGEEDEADLT DWNLPLAFMK KRHCEKIEGS KSLAQSWRMK DRMKTVSVA LVLCLNVGVD PPDVVKTTPC ARLECWIDPL SMGPQKALET IGANLQKQYE NWQPRARYKQ SLDPTVDEVK K LCTSLRRN AKEERVLFHY NGHGVPRPTV NGEVWVFNKN YTQYIPLSIY DLQTWMGSPS IFVYDCSNAG LIVKSFKQFA LQ REQELEV AAINPNHPLA QMPLPPSMKN CIQLAACEAT ELLPMIPDLP ADLFTSCLTT PIKIALRWFC MQKCVSLVPG VTL DLIEKI PGRLNDRRTP LGELNWIFTA ITDTIAWNVL PRDLFQKLFR QDLLVASLFR NFLLAERIMR SYNCTPVSSP RLPP TYMHA MWQAWDLAVD ICLSQLPTII EEGTAFRHSP FFAEQLTAFQ VWLTMGVENR NPPEQLPIVL QVLLSQVHRL RALDL LGRF LDLGPWAVSL ALSVGIFPYV LKLLQSSARE LRPLLVFIWA KILAVDSSCQ ADLVKDNGHK YFLSVLADPY MPAEHR TMT AFILAVIVNS YHTGQEACLQ GNLIAICLEQ LNDPHPLLRQ WVAICLGRIW QNFDSARWCG VRDSAHEKLY SLLSDPI PE VRCAAVFALG TFVGNSAERT DHSTTIDHNV AMMLAQLVSD GSPMVRKELV VALSHLVVQY ESNFCTVALQ FIEEEKNY A LPSPATTEGG SLTPVRDSPC TPRLRSVSSY GNIRAVATAR SLNKSLQNLS LTEESGGAVA FSPGNLSTSS SASSTLGSP ENEEHILSFE TIDKMRRASS YSSLNSLIGV SFNSVYTQIW RVLLHLAADP YPEVSDVAMK VLNSIAYKAT VNARPQRVLD TSSLTQSAP ASPTNKGVHI HQAGGSPPAS STSSSSLTND VAKQPVSRDL PSGRPGTTGP AGAQYTPHSH QFPRTRKMFD K GPEQTADD ADDAAGHKSF ISATVQTGFC DWSARYFAQP VMKIPEEHDL ESQIRKEREW RFLRNSRVRR QAQQVIQKGI TR LDDQIFL NRNPGVPSVV KFHPFTPCIA VADKDSICFW DWEKGEKLDY FHNGNPRYTR VTAMEYLNGQ DCSLLLTATD DGA IRVWKN FADLEKNPEM VTAWQGLSDM LPTTRGAGMV VDWEQETGLL MSSGDVRIVR IWDTDREMKV QDIPTGADSC VTSL SCDSH RSLIVAGLGD GSIRVYDRRM ALSECRVMTY REHTAWVVKA SLQKRPDGHI VSVSVNGDVR IFDPRMPESV NVLQI VKGL TALDIHPQAD LIACGSVNQF TAIYNSSGEL INNIKYYDGF MGQRVGAISC LAFHPHWPHL AVGSNDYYIS VYSVEK RVR

UniProtKB: Regulatory-associated protein of mTOR

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Macromolecule #2: Lateral signaling target protein 2 homolog

MacromoleculeName: Lateral signaling target protein 2 homolog / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 96.604477 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MMNRFRKWLY KPKRSDPQLL ARFYYADEEL NQVAAELDSL DGRKDPQRCT LLVSQFRSCQ DNVLNIINQI MDECIPQDRA PRDFCVKFP EEIRHDNLAG QLWFGAECLA AGSIIMNREL ESMAMRPLAK ELTRSLEDVR GALRDQALRD LNTYTEKMRE A LRHFDVLF ...String:
MMNRFRKWLY KPKRSDPQLL ARFYYADEEL NQVAAELDSL DGRKDPQRCT LLVSQFRSCQ DNVLNIINQI MDECIPQDRA PRDFCVKFP EEIRHDNLAG QLWFGAECLA AGSIIMNREL ESMAMRPLAK ELTRSLEDVR GALRDQALRD LNTYTEKMRE A LRHFDVLF AEFELSYVSA MVPVKSPREY YVQQEVIVLF CETVERALDF GYLTQDMIDD YEPALMFSIP RLAIVCGLVV YA DGPLNLD RKVEDMSELF RPFHTLLRKI RDLLQTLTEE ELHTLERNLC ISQDVEFPIR ADVQGPAALA PALSAPLPPE GPL SAKAKD PDAELACSMQ YDDQELEQLS RMVHRAGDEM SSLLSPPIAC QSPAHRPGAE GSPGGEASPG RPRLRSGSDE EERV FFMDD VEGTAEALAR PESPAGPFGW AGSTWADPQE KGQGGPGGAA GISLPASEKE EDLSNNNLEA EGTDGASLAG TSSCS CLDS RLHLDGWEVG ADDAETAEMI AHRTGGMKLS ATVIFNPKSP TSLDSAVATQ EAASEPVAEG MDGGPHKLST GATNCL LHS CVCCGSCGDS REDVVERLRE KCSPGGVIGA SYAAGLAKAS DRAPERQEEA PPPSEDASNG REPKAPTSDK CLPHTSG SQ VDTASGLQGE AGVAGQQEPE ARELHAGSPS AHEAPQALSG SSSSTAGSCS SDKMGPEAAP AATHAAPQAT REKIRSRF H GSHDLIHRLF VCISGVADQL QTNYASDLRS ILKTLFEVMA TKPETDDKEK LRKVTQTLRS AALEDCALCQ ETLSSSELA AKTRDGDFED PPEWVPDEAC GFCTACKAPF TVIRRKHHCR SCGKIFCSRC SSHSAPLPRY GQVKPVRVCT HCYMFHVTPF YSDKAGL

UniProtKB: Lateral signaling target protein 2 homolog

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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

Concentration1 mg/mL
BufferpH: 8
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 4719 / Average electron dose: 43.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1057805
Startup modelType of model: OTHER / Details: CryoSPARC ab-initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 545524
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7peb


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9f43:
cryo-EM structure of human LST2 bound to human mTOR complex 1, focused on RAPTOR

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