ArticleThe Journal of biological chemistry2018
Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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Who cites it
33 citing papers in PubMed, 45 citations in OpenAlex.
- Complex assembly and activity states as multifaceted protein attributes explaining phenotypic variability.Molecular systems biology · 2026Article
- IQGAP1 and IQGAP3 are critical host factors for Marburg virus replication, nucleocapsid transport, and cell-to-cell spread.Cellular and molecular life sciences : CMLS · 2026Article
- Complex Assembly and Activity States as Multifaceted Protein Attributes Explaining Phenotypic Variability.bioRxiv : the preprint server for biology · 2025Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- Article
- Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor.Disease models & mechanisms · 2023Article
- Computational approaches for the design of modulators targeting protein-protein interactions.Expert opinion on drug discovery · 2023Review
- The Antithetic Roles of IQGAP2 and IQGAP3 in Cancers.Cancers · 2023Review
- Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire.Protein science : a publication of the Protein Society · 2023Article
- Discovery of small molecule inhibitors that effectively disrupt IQGAP1-Cdc42 interaction in breast cancer cells.Scientific reports · 2022Article
- Tension of plus-end tracking protein Clip170 confers directionality and aggressiveness during breast cancer migration.Cell death & disease · 2022Article
- CDC42-IQGAP Interactions Scrutinized: New Insights into the Binding Properties of the GAP-Related Domain.International journal of molecular sciences · 2022Article
- The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia.Biophysical journal · 2022Article
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Role of IQ Motif-Containing GTPase-Activating Proteins in Hepatocellular Carcinoma.Frontiers in oncology · 2022Review
- Selectivity Determinants of RHO GTPase Binding to IQGAPs.International journal of molecular sciences · 2021Article
- The structural basis of Akt PH domain interaction with calmodulin.Biophysical journal · 2021Article
- Mechanistic Differences of Activation of Rac1The journal of physical chemistry. B · 2021Article
- Active and Inactive Cdc42 Differ in Their Insert Region Conformational Dynamics.Biophysical journal · 2021Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
IQ motif-containing GTPase-activating proteins (IQGAPs) are scaffolding proteins playing central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTP-bound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Ex-domain and the RasGAP site of the GTPase-activating protein (GAP)-related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert-loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.
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