ArticleBiophysical journal2021
Active and Inactive Cdc42 Differ in Their Insert Region Conformational Dynamics.
Article in Biophysical journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- How Functional Variants Reconfigure the Rac2 Conformational Landscape.The journal of physical chemistry. B · 2026Article
- Hearing loss associated with CDC42 in mice and humans (Takenouchi-Kosaki syndrome): CDC42 and RHOQ synergistically function in cochlear hair cells.The Journal of biological chemistry · 2026Article
- How Functional Variants Reconfigure the Rac2 Conformational Landscape.bioRxiv : the preprint server for biology · 2026Article
- An evolutionarily conserved salt bridge stabilizes the active site for GTP hydrolysis in Rho GTPases.The Journal of biological chemistry · 2026Article
- Targeting Cdc42: Novel Approaches in Cardiovascular Disorders.Current protein & peptide science · 2026Review
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- M-Ras distinct activation scenarios: A mechanistic outlook and targeting.Computational and structural biotechnology journal · 2025Article
- Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.Neurochemistry international · 2024Review
- Tumor-derived RHOA mutants interact with effectors in the GDP-bound state.Nature communications · 2024Article
- A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3β/β-catenin Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Salmonella engages CDC42 effector protein 1 for intracellular invasion.Journal of cellular physiology · 2024Article
- Computational Investigation of Selected Spike Protein Mutations in SARS-CoV-2: Delta, Omicron, and Some Circulating Subvariants.Pathogens (Basel, Switzerland) · 2023Article
- Cancer and Autism: How PTEN Mutations Degrade Function at the Membrane and Isoform Expression in the Human Brain.Journal of molecular biology · 2023Article
- Activation Mechanism of RhoA Caused by Constitutively Activating Mutations G14V and Q63L.International journal of molecular sciences · 2022Article
- CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain.International journal of molecular sciences · 2022Article
- Possible Role of Extracellular Vesicles in Hepatotoxicity of Acetaminophen.International journal of molecular sciences · 2022Article
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Regulation of Cdc42 signaling by the dopamine D2 receptor in a mouse model of Parkinson's disease.Aging cell · 2022Article
- Molecular subversion of Cdc42 signalling in cancer.Biochemical Society transactions · 2021Review
- The mechanism of activation of monomeric B-Raf V600E.Computational and structural biotechnology journal · 2021Article
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Authors and funding
3 authors at 3 institutions in 2 countries.
Funding
Abstract
Cell division control protein 42 homolog (Cdc42) protein, a Ras superfamily GTPase, regulates cellular activities, including cancer progression. Using all-atom molecular dynamics (MD) simulations and essential dynamic analysis, we investigated the structure and dynamics of the catalytic domains of GDP-bound (inactive) and GTP-bound (active) Cdc42 in solution. We discovered substantial differences in the dynamics of the inactive and active forms, particularly in the "insert region" (residues 122-135), which plays a role in Cdc42 activation and binding to effectors. The insert region has larger conformational flexibility in the GDP-bound Cdc42 than in the GTP-bound Cdc42. The G2 loop and switch I at the effector lobe of the catalytic domain exhibit large conformational changes in both the GDP- and the GTP-bound systems, but in the GTP-bound Cdc42, the switch I interactions with GTP are retained. Oncogenic mutations were identified in the Ras superfamily. In Cdc42, the G12V and Q61L mutations decrease the GTPase activity. We simulated these mutations in both GDP- and GTP-bound Cdc42. Although the overall structural organization is quite similar between the wild type and the mutants, there are small differences in the conformational dynamics, especially in the two switch regions. Taken together, the G12V and Q61L mutations may play a role similar to their K-Ras counterparts in nucleotide binding and activation. The conformational differences, which are mainly in the insert region and, to a lesser extent, in the switch regions flanking the nucleotide binding site, can shed light on binding and activation. We propose that the differences are due to a network of hydrogen bonds that gets disrupted when Cdc42 is bound to GDP, a disruption that does not exist in other Rho GTPases. The differences in the dynamics between the two Cdc42 states suggest that the inactive conformation has reduced ability to bind to effectors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.