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- PDB-9h75: NMR solution structure of the GEFH1 C1 domain -

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Basic information

Entry
Database: PDB / ID: 9h75
TitleNMR solution structure of the GEFH1 C1 domain
ComponentsRho guanine nucleotide exchange factor 2
KeywordsPROTEIN BINDING / STRUCTURE FROM CYANA 3.98.4
Function / homology
Function and homology information


asymmetric neuroblast division / negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress / cellular response to muramyl dipeptide / positive regulation of neuron migration / negative regulation of microtubule depolymerization / regulation of Rho protein signal transduction / negative regulation of necroptotic process / cellular hyperosmotic response / regulation of small GTPase mediated signal transduction / positive regulation of peptidyl-tyrosine phosphorylation ...asymmetric neuroblast division / negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress / cellular response to muramyl dipeptide / positive regulation of neuron migration / negative regulation of microtubule depolymerization / regulation of Rho protein signal transduction / negative regulation of necroptotic process / cellular hyperosmotic response / regulation of small GTPase mediated signal transduction / positive regulation of peptidyl-tyrosine phosphorylation / RHOB GTPase cycle / NRAGE signals death through JNK / RHOA GTPase cycle / bicellular tight junction / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of neuron differentiation / guanyl-nucleotide exchange factor activity / actin filament organization / intracellular protein transport / : / positive regulation of interleukin-6 production / small GTPase binding / ruffle membrane / spindle / cell morphogenesis / positive regulation of tumor necrosis factor production / cellular response to tumor necrosis factor / G alpha (12/13) signalling events / regulation of cell population proliferation / cytoplasmic vesicle / microtubule binding / vesicle / microtubule / cytoskeleton / innate immune response / focal adhesion / Golgi apparatus / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / cytosol / cytoplasm
Similarity search - Function
ARHGEF2, PH domain / : / ARHGEF1-like, PH domain / PH domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Zinc finger phorbol-ester/DAG-type signature. ...ARHGEF2, PH domain / : / ARHGEF1-like, PH domain / PH domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily
Similarity search - Domain/homology
Rho guanine nucleotide exchange factor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics
AuthorsChoi, S.R. / Gossert, A.D. / Steinmetz, M.O.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation31003A_166608 Switzerland
CitationJournal: Cell / Year: 2025
Title: Structural basis of microtubule-mediated signal transduction.
Authors: Sung Ryul Choi / Thorsten B Blum / Matteo Giono / Bibhas Roy / Ioannis Vakonakis / Dominic Schmid / Nicole Oelgarth / Apisha Ranganathan / Alvar D Gossert / G V Shivashankar / Alfred ...Authors: Sung Ryul Choi / Thorsten B Blum / Matteo Giono / Bibhas Roy / Ioannis Vakonakis / Dominic Schmid / Nicole Oelgarth / Apisha Ranganathan / Alvar D Gossert / G V Shivashankar / Alfred Zippelius / Michel O Steinmetz /
Abstract: Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis ...Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.
History
DepositionOct 26, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 14, 2026Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Rho guanine nucleotide exchange factor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)8,3823
Polymers8,2511
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 100target function
RepresentativeModel #1target function

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Components

#1: Protein Rho guanine nucleotide exchange factor 2 / Guanine nucleotide exchange factor H1 / GEF-H1 / Microtubule-regulated Rho-GEF / Proliferating cell ...Guanine nucleotide exchange factor H1 / GEF-H1 / Microtubule-regulated Rho-GEF / Proliferating cell nucleolar antigen p40


Mass: 8250.749 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARHGEF2, KIAA0651, LFP40 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q92974
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic13D HN(CA)CB
121isotropic13D CBCA(CO)NH
131isotropic23D (H)CCH-TOCSY
141isotropic13D 1H-13C NOESY
151isotropic13D 1H-15N NOESY
161isotropic12D 1H-13C HSQC
171isotropic12D 1H-15N HSQC

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Sample preparation

DetailsType: solution
Contents: 1.0 mM [U-13C; U-15N] GEFH1 28-100, 150 mM NaCl, 25 mM NaPi, 10 % v/v [U-2H] D2O, 90 % v/v H2O, 90% H2O/10% D2O
Label: u-13C,15N GEFH1-C1 / Solvent system: 90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
1.0 mMGEFH1 28-100[U-13C; U-15N]1
150 mMNaClnatural abundance1
25 mMNaPinatural abundance1
10 % v/vD2O[U-2H]1
90 % v/vH2Onatural abundance1
Sample conditionsIonic strength: 175 mM / Label: Conditions_1 / pH: 7.2 / Pressure: 1 bar / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE NEOBrukerAVANCE NEO7001
Bruker AVANCE III HDBrukerAVANCE III HD6002

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Processing

NMR software
NameDeveloperClassification
CARAKeller and Wuthrichchemical shift assignment
CYANAGuntert, Mumenthaler and Wuthrichstructure calculation
AmberCase, Darden, Cheatham III, Simmerling, Wang, Duke, Luo, ... and Kollmanrefinement
CcpNmr AnalysisCCPNpeak picking
RefinementMethod: molecular dynamics / Software ordinal: 3
NMR representativeSelection criteria: target function
NMR ensembleConformer selection criteria: target function / Conformers calculated total number: 100 / Conformers submitted total number: 20

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