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- EMDB-74549: Autoinhibited P-Rex2 Local Refinement of Whole Particle -

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Basic information

Entry
Database: EMDB / ID: EMD-74549
TitleAutoinhibited P-Rex2 Local Refinement of Whole Particle
Map dataLocal refinement of the whole particle
Sample
  • Organelle or cellular component: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-Rex2)
KeywordsRho guanine-nucleotide exchange factor / autoinhibition / SIGNALING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.4 Å
AuthorsAnderson LK / Cash JN
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM146664 United States
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)UL1 TR001860 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R24GM154185 United States
CitationJournal: J Biol Chem / Year: 2026
Title: The Rho guanine-nucleotide exchange factor P-Rex2 exhibits structural and regulatory features distinct from the related RhoGEF P-Rex1.
Authors: Lauren K Anderson / Rohan Marde / Grace Muma / Veda Nayak / Chi Phan / Sheng Li / Jennifer N Cash /
Abstract: Rho guanine-nucleotide exchange factors (RhoGEFs) activate small GTPases to drive cytoskeletal rearrangement, cell motility, and proliferation. The phosphatidylinositol-3,4,5-trisphosphate (PIP)- ...Rho guanine-nucleotide exchange factors (RhoGEFs) activate small GTPases to drive cytoskeletal rearrangement, cell motility, and proliferation. The phosphatidylinositol-3,4,5-trisphosphate (PIP)-dependent Rac exchanger (P-Rex) subfamily of RhoGEFs includes P-Rex1 and P-Rex2 which, when misregulated, contribute to cancer progression and metastasis. P-Rex activity is controlled by accessory domains that maintain the protein in a cytosolic, autoinhibited state until activated by the lipid PIP and G protein βγ subunits. While P-Rex1 autoinhibition has been structurally and biochemically characterized, P-Rex2 has remained largely unexplored. Furthermore, despite high sequence similarity and domain conservation, P-Rex homologs differ in substrate specificity and regulatory interactions, and the molecular basis for these divergences is unknown. Here, we have taken an integrative structural biology approach to investigate these gaps. Using cryo-EM, we determined the first structure of full-length P-Rex2 to moderate resolution, revealing that, while the overall structure closely resembles that of P-Rex1, there is a substantial repositioning of the N-terminal module relative to the C-terminal core. This may play a key role in precluding the intramolecular interactions between the N- and C-terminal domains that are observed in autoinhibited P-Rex1. Hydrogen-deuterium exchange mass spectrometry revealed that, unlike P-Rex1, P-Rex2 dynamics are unaffected by IP, the headgroup of PIP. SEC-SAXS data support that the N-terminal module itself is less dynamic, and biochemical assays show that P-Rex2 may be differently regulated by autoinhibition, likely through a mechanism divergent from P-Rex1. These findings uncover unique features in the molecular mechanisms of P-Rex2 regulation.
History
DepositionDec 17, 2025-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateJul 1, 2026-
Current statusJul 1, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74549.png

Downloads & links

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Map

FileDownload / File: emd_74549.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement of the whole particle
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 448 pix.
= 326.861 Å		0.73 Å/pix.
x 448 pix.
= 326.861 Å		0.73 Å/pix.
x 448 pix.
= 326.861 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.7296 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.31468275 - 0.6198128
Average (Standard dev.)-0.00003799139 (±0.0074375556)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 326.8608 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_74549_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of the whole particle local refinement

Fileemd_74549_half_map_1.map
AnnotationHalf map of the whole particle local refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map of the whole particle local refinement

Fileemd_74549_half_map_2.map
AnnotationHalf map of the whole particle local refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger ...

EntireName: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-Rex2)
Components
  • Organelle or cellular component: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-Rex2)

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Supramolecule #1: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger ...

SupramoleculeName: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-Rex2)
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 183 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

Concentration0.4 mg/mL
BufferpH: 8
Details: 20 mM HEPES (pH 8.0), 100 mM NaCl, 2 mM dithiothreitol (DTT), 0.07 mM n-Dodecyl-B-D-Maltoside (DDM)
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 2 / Number real images: 19792 / Average electron dose: 50.0 e/Å2
Details: 12070 untilted micrographs and 7722 micrographs with 35 tilt
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4322000
Details: 2184088 particles from tilted micrographs and 2137912 particles from untilted micrographs
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE / Details: Ab-initio in cryosparc
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: PHENIX / Number images used: 128298
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
ChainDetails
residue_range: 15-467, source_name: AlphaFold, initial_model_type: in silico modelP-Rex2 N-terminal module
residue_range: 473-1606, source_name: AlphaFold, initial_model_type: in silico modelP-Rex2 core
DetailsAlphaFold server used to generate individual initial models of the core and N-terminal module which were rigid body fit to the composite map and further refined in Coot.
RefinementProtocol: RIGID BODY FIT

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