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- EMDB-25526: Localised reconstruction of the C-terminal half of P-Rex 1 (PI(3,... -

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Entry
Database: EMDB / ID: EMD-25526
TitleLocalised reconstruction of the C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)
Map data
Sample
  • Complex: C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)
Keywordsguanine nucleotide exchange factor / metastasis / plasma membrane / Rho GTPase signalling / ONCOPROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLupton CJ / Bayly-Jones C / Ellisdon AM
Funding support Australia, 2 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1146578 Australia
National Health and Medical Research Council (NHMRC, Australia)APP1128120 Australia
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.
Authors: Yong-Gang Chang / Christopher J Lupton / Charles Bayly-Jones / Alastair C Keen / Laura D'Andrea / Christina M Lucato / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / James C ...Authors: Yong-Gang Chang / Christopher J Lupton / Charles Bayly-Jones / Alastair C Keen / Laura D'Andrea / Christina M Lucato / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / James C Whisstock / Michelle L Halls / Andrew M Ellisdon /
Abstract: P-Rex (PI(3,4,5)P-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by ...P-Rex (PI(3,4,5)P-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by Gβγ and PI(3,4,5)P binding and dysregulated in cancer. Here, we use X-ray crystallography, cryogenic electron microscopy and crosslinking mass spectrometry to determine the structural basis of human P-Rex1 autoinhibition. P-Rex1 has a bipartite structure of N- and C-terminal modules connected by a C-terminal four-helix bundle that binds the N-terminal Pleckstrin homology (PH) domain. In the N-terminal module, the Dbl homology (DH) domain catalytic surface is occluded by the compact arrangement of the DH-PH-DEP1 domains. Structural analysis reveals a remarkable conformational transition to release autoinhibition, requiring a 126° opening of the DH domain hinge helix. The off-axis position of Gβγ and PI(3,4,5)P binding sites further suggests a counter-rotation of the P-Rex1 halves by 90° facilitates PH domain uncoupling from the four-helix bundle, releasing the autoinhibited DH domain to drive Rho GTPase signaling.
History
DepositionNov 24, 2021-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25526.png

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Map

FileDownload / File: emd_25526.map.gz / Format: CCP4 / Size: 14.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.34564 Å
Density
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.0015311979 - 1.9974254
Average (Standard dev.)0.0029405314 (±0.040515598)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions156156156
Spacing156156156
CellA=B=C: 209.91983 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_25526_msk_1.map
Projections & Slices
AxesZYX

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Additional map: #1

Fileemd_25526_additional_1.map
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Half map: #2

Fileemd_25526_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_25526_half_map_2.map
Projections & Slices
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Sample components

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Entire : C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)

EntireName: C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)
Components
  • Complex: C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)

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Supramolecule #1: C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)

SupramoleculeName: C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 191 KDa

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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

Concentration0.18 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF
Details: Localised reconstruction of the C-terminal half of P-Rex 1 (PI(3,4,5)P3-dependent Rac Exchanger 1)
Number images used: 123896
FSC plot (resolution estimation)

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