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- EMDB-51182: cryoEM map of human PHLPP2 -

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Basic information

Entry
Database: EMDB / ID: EMD-51182
TitlecryoEM map of human PHLPP2
Map data
Sample
  • Complex: recombinant human PHLPP2
    • Protein or peptide: PH domain leucine-rich repeat-containing protein phosphatase 2
KeywordsPHLPP2 / Pseudophosphatase / UNKNOWN FUNCTION
Function / homology
Function and homology information


Negative regulation of the PI3K/AKT network / photoreceptor outer segment membrane / histone H2AXS140 phosphatase activity / RNA polymerase II CTD heptapeptide repeat Y1 phosphatase activity / RNA polymerase II CTD heptapeptide repeat T4 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MAP kinase serine/threonine phosphatase activity / calmodulin-dependent protein phosphatase activity ...Negative regulation of the PI3K/AKT network / photoreceptor outer segment membrane / histone H2AXS140 phosphatase activity / RNA polymerase II CTD heptapeptide repeat Y1 phosphatase activity / RNA polymerase II CTD heptapeptide repeat T4 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity / RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity / MAP kinase serine/threonine phosphatase activity / calmodulin-dependent protein phosphatase activity / myosin phosphatase activity / protein-serine/threonine phosphatase / intercellular bridge / photoreceptor inner segment / hippocampus development / mitotic spindle / intracellular signal transduction / cilium / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / PHLPP protein RA domain / Protein phosphatase 2C / Serine/threonine phosphatases, family 2C, catalytic domain / : / PPM-type phosphatase domain profile. / PPM-type phosphatase-like domain / PPM-type phosphatase-like domain superfamily / Leucine Rich repeat / Leucine Rich Repeat ...: / PHLPP protein RA domain / Protein phosphatase 2C / Serine/threonine phosphatases, family 2C, catalytic domain / : / PPM-type phosphatase domain profile. / PPM-type phosphatase-like domain / PPM-type phosphatase-like domain superfamily / Leucine Rich repeat / Leucine Rich Repeat / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
PH domain leucine-rich repeat-containing protein phosphatase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.0 Å
AuthorsSiess K / Grishkovskaya I / Haselbach D / Leonard TA
Funding support Austria, United Kingdom, 4 items
OrganizationGrant numberCountry
Austrian Science FundP33066 Austria
Austrian Science FundP36212 Austria
Austrian Science FundW1261 Austria
Diamond Light SourceBI25222-3 United Kingdom
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor.
Authors: Tarik Husremović / Vanessa Meier / Lucas Piëch / Katharina M Siess / Sumire Antonioli / Irina Grishkovskaya / Nikoleta Kircheva / Silvia E Angelova / Karoline Wenzl / Andreas Brandstätter ...Authors: Tarik Husremović / Vanessa Meier / Lucas Piëch / Katharina M Siess / Sumire Antonioli / Irina Grishkovskaya / Nikoleta Kircheva / Silvia E Angelova / Karoline Wenzl / Andreas Brandstätter / Jiri Veis / Fran Miočić-Stošić / Dorothea Anrather / Markus Hartl / Linda Truebestein / Luis M Cerron-Alvan / Martin Leeb / Bojan Žagrović / Stephan Hann / Christoph Bock / Egon Ogris / Todor Dudev / Nicholas A T Irwin / David Haselbach / Thomas A Leonard /
Abstract: The phosphoinositide 3-kinase (PI3K) pathway is a major regulator of cell and organismal growth. Consequently, hyperactivation of PI3K and its downstream effector kinase, Akt, is observed in many ...The phosphoinositide 3-kinase (PI3K) pathway is a major regulator of cell and organismal growth. Consequently, hyperactivation of PI3K and its downstream effector kinase, Akt, is observed in many human cancers. Pleckstrin homology domain leucine-rich repeat-containing protein phosphatases (PHLPP), two paralogous members of the metal-dependent protein phosphatase family, have been reported as negative regulators of Akt signaling and, therefore, tumor suppressors. However, the stoichiometry and identity of the bound metal ion(s), mechanism of action, and enzymatic specificity of these proteins are not known. Seeking to fill these gaps in our understanding of PHLPP biology, we unexpectedly found that PHLPP2 has no catalytic activity in vitro. Instead, we found that PHLPP2 is a pseudophosphatase with a single zinc ion bound in its catalytic center. Furthermore, we found that cancer genomics data do not support the proposed role of PHLPP1 or PHLPP2 as tumor suppressors. Phylogenetic analyses revealed an ancestral phosphatase that arose more than 1,000 Mya, but that lost activity at the base of the metazoan lineage. Surface conservation indicates that while PHLPP2 has lost catalytic activity, it may have retained substrate binding. Finally, using phylogenomics, we identify coevolving genes consistent with a scaffolding role for PHLPP2 on membranes. In summary, our results provide a molecular explanation for the inconclusive results that have hampered research on PHLPP and argue for a focus on the noncatalytic roles of PHLPP1 and PHLPP2.
History
DepositionJul 28, 2024-
Header (metadata) releaseMar 19, 2025-
Map releaseMar 19, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51182.png

Downloads & links

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Map

FileDownload / File: emd_51182.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.24 Å/pix.
x 160 pix.
= 198. Å		1.24 Å/pix.
x 160 pix.
= 198. Å		1.24 Å/pix.
x 160 pix.
= 198. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2375 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00591
Minimum - Maximum-0.0071301265 - 0.020207856
Average (Standard dev.)0.000087153974 (±0.001040512)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 198.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_51182_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_51182_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : recombinant human PHLPP2

EntireName: recombinant human PHLPP2
Components
  • Complex: recombinant human PHLPP2
    • Protein or peptide: PH domain leucine-rich repeat-containing protein phosphatase 2

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Supramolecule #1: recombinant human PHLPP2

SupramoleculeName: recombinant human PHLPP2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140 KDa

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Macromolecule #1: PH domain leucine-rich repeat-containing protein phosphatase 2

MacromoleculeName: PH domain leucine-rich repeat-containing protein phosphatase 2
type: protein_or_peptide / ID: 1 / Enantiomer: DEXTRO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GARMKRNGSR NCLNRRSRFG SRERDWLRED VKRGCVYLYG ADTTTATTTT TTSSSSSSSS SSSDLHLVLC TVETPASEIC AGEGRESLYL QLHGDLVRRL EPTERPLQIV YDYLSRLGFD DPVRIQEEAT NPDLGCMIRF YGEKPCHMDR LDRILLSGIY NVRKGKTQLH ...String:
GARMKRNGSR NCLNRRSRFG SRERDWLRED VKRGCVYLYG ADTTTATTTT TTSSSSSSSS SSSDLHLVLC TVETPASEIC AGEGRESLYL QLHGDLVRRL EPTERPLQIV YDYLSRLGFD DPVRIQEEAT NPDLGCMIRF YGEKPCHMDR LDRILLSGIY NVRKGKTQLH KWAERLVVLC GTCLIVSSVK DCQTGKMHIL PLVGGKIEEV KRRQYSLAFS SAGAQAQTYH VSFETLAEYQ RWQRQASKVV SQRISTVDLS CYSLEEVPEH LFYSQDITYL NLRHNFMQLE RPGGLDTLYK FSQLKGLNLS HNKLGLFPIL LCEISTLTEL NLSCNGFHDL PSQIGNLLNL QTLCLDGNFL TTLPEELGNL QQLSSLGISF NNFSQIPEVY EKLTMLDRVV MAGNCLEVLN LGVLNRMNHI KHVDLRMNHL KTMVIENLEG NKHITHVDLR DNRLTDLDLS SLCSLEQLHC GRNQLRELTL SGFSLRTLYA SSNRLTAVNV YPVPSLLTFL DLSRNLLECV PDWACEAKKI EVLDVSYNLL TEVPVRILSS LSLRKLMLGH NHVQNLPTLV EHIPLEVLDL QHNALTRLPD TLFSKALNLR YLNASANSLE SLPSACTGEE SLSMLQLLYL TNNLLTDQCI PVLVGHLHLR ILHLANNQLQ TFPASKLNKL EQLEELNLSG NKLKTIPTTI ANCKRLHTLV AHSNNISIFP EILQLPQIQF VDLSCNDLTE ILIPEALPAT LQDLDLTGNT NLVLEHKTLD IFSHITTLKI DQKPLPTTDS TVTSTFWSHG LAEMAGQRNK LCVSALAMDS FAEGVGAVYG MFDGDRNEEL PRLLQCTMAD VLLEEVQQST NDTVFMANTF LVSHRKLGMA GQKLGSSALL CYIRPDTADP ASSFSLTVAN VGTCQAVLCR GGKPVPLSKV FSLEQDPEEA QRVKDQKAII TEDNKVNGVT CCTRMLGCTY LYPWILPKPH ISSTPLTIQD ELLILGNKAL WEHLSYTEAV NAVRHVQDPL AAAKKLCTLA QSYGCQDNVG AMVVYLNIGE EGCTCEMNGL TLPGPVGFAS TTTIKDAPKP ATPSSSSGIA SEFSSEMSTS EVSSEVGSTA SDEHNAGGLD TALLPRPERR CSLHPTPTSG LFQRQPSSAT FSSNQSDNGL DSDDDQPVEG VITNGSKVEV EVDIHCCRGR DLENSPPLIE SSPTLCSEEH ARGSCFGIRR QNSVNSGMLL PMSKDRMELQ KSPSTSCLYG KKLSNGSIVP LEDSLNLIEV ATEVPKRKTG YFAAPTQMEP EDQFVVPHDL EEEVKEQMKQ HQDSRLEPEP HEEDRTEPPE EFDTAL

UniProtKB: PH domain leucine-rich repeat-containing protein phosphatase 2

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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

Concentration0.1 mg/mL
BufferpH: 6.5
Component:
ConcentrationFormulaName
50.0 mMMES2-(N-morpholino)ethanesulfonic acid
150.0 mMNaClsodium chloride
0.1 %NP40Nonidet P-40
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber temperature: 277 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 35.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.7 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 958089
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 6.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 118375
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 5)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT

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