ArticleThe Journal of biological chemistry2015
GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 90 citations in OpenAlex.
- G12 mutations rewire allosteric communication at the Ras-RalGDS interface.Biophysical journal · 2026Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- In Silico Identification of Putative Allosteric Pockets and Inhibitors for the KRASG13D-SOS1 Complex in Cancer Therapy.International journal of molecular sciences · 2025Article
- Advances and Challenges in RAS Signaling Targeted Therapy in Leukemia.Molecular cancer therapeutics · 2025Review
- RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms.Journal of hematology & oncology · 2024Review
- Insight into structural dynamics involved in activation mechanism of full length KRAS wild type and P-loop mutants.Heliyon · 2024Article
- Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.Biophysical journal · 2024Article
- Decrypting Allostery in Membrane-Bound K-Ras4B Using ComplementaryJournal of the American Chemical Society · 2024Article
- Computer-Aided Drug Design Boosts RAS Inhibitor Discovery.Molecules (Basel, Switzerland) · 2022Review
- Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASFrontiers in oncology · 2022Article
- Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect.Frontiers in molecular biosciences · 2022Article
- Ras isoform-specific expression, chromatin accessibility, and signaling.Biophysical reviews · 2021Review
- Emerging strategies to target RAS signaling in human cancer therapy.Journal of hematology & oncology · 2021Review
- Design and structural characterization of autoinhibition-compromised full-length Ran.Signal transduction and targeted therapy · 2021Article
- Targeted Degradation of Oncogenic KRASACS central science · 2020Article
- The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling.Biophysical journal · 2020Article
- Nucleotide-Specific Autoinhibition of Full-Length K-Ras4B Identified by Extensive Conformational Sampling.Frontiers in molecular biosciences · 2020Article
- The quaternary assembly of KRas4B with Raf-1 at the membrane.Computational and structural biotechnology journal · 2020Article
- The current understanding of KRAS protein structure and dynamics.Computational and structural biotechnology journal · 2020Review
- The Hypervariable Region of K-Ras4B Governs Molecular Recognition and Function.International journal of molecular sciences · 2019Review
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Authors and funding
6 authors at 3 institutions in 4 countries.
Funding
Abstract
K-Ras4B, a frequently mutated oncogene in cancer, plays an essential role in cell growth, differentiation, and survival. Its C-terminal membrane-associated hypervariable region (HVR) is required for full biological activity. In the active GTP-bound state, the HVR interacts with acidic plasma membrane (PM) headgroups, whereas the farnesyl anchors in the membrane; in the inactive GDP-bound state, the HVR may interact with both the PM and the catalytic domain at the effector binding region, obstructing signaling and nucleotide exchange. Here, using molecular dynamics simulations and NMR, we aim to figure out the effects of nucleotides (GTP and GDP) and frequent (G12C, G12D, G12V, G13D, and Q61H) and infrequent (E37K and R164Q) oncogenic mutations on full-length K-Ras4B. The mutations are away from or directly at the HVR switch I/effector binding site. Our results suggest that full-length wild-type GDP-bound K-Ras4B (K-Ras4B(WT)-GDP) is in an intrinsically autoinhibited state via tight HVR-catalytic domain interactions. The looser association in K-Ras4B(WT)-GTP may release the HVR. Some of the oncogenic mutations weaken the HVR-catalytic domain association in the K-Ras4B-GDP/-GTP bound states, which may facilitate the HVR disassociation in a nucleotide-independent manner, thereby up-regulating oncogenic Ras signaling. Thus, our results suggest that mutations can exert their effects in more than one way, abolishing GTP hydrolysis and facilitating effector binding.
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