ArticleBiophysical journal2019
KRAS Prenylation Is Required for Bivalent Binding with Calmodulin in a Nucleotide-Independent Manner.
Article in Biophysical journal, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 54 citations in OpenAlex.
- Regulation of Membrane Association and Downstream Effector Interaction of K-Ras by Its Hypervariable Region.Membranes · 2026Article
- Crosstalk between protein lipidation and ubiquitination in tumor biology.Apoptosis : an international journal on programmed cell death · 2026Review
- Review
- Regulation of the formin INF2 by actin monomers and calcium/calmodulin.The Journal of cell biology · 2026Article
- Protein Prenylation Makeovers in Plants: Insights into Substrate Diversification.International journal of molecular sciences · 2025Review
- Structural basis for LZTR1 recognition of RAS GTPases for degradation.Science (New York, N.Y.) · 2025Article
- Targeting KRAS: from metabolic regulation to cancer treatment.Molecular cancer · 2025Review
- KRas4b-Calmodulin Interaction with Membrane Surfaces: Role of Headgroup, Acyl Chain, and Electrostatics.Biochemistry · 2024Article
- Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.bioRxiv : the preprint server for biology · 2024Article
- Natural Product Graveoline Modulates Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Membrane Association: Insights from Advanced Spectroscopic Studies.ACS pharmacology & translational science · 2024Article
- A Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement.Analytical chemistry · 2024Article
- Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion.Biomedicines · 2024Article
- Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties.Science advances · 2024Article
- Determining KRAS4B-Targeting Compound Specificity by Top-Down Mass Spectrometry.Methods in molecular biology (Clifton, N.J.) · 2024Article
- 1D and 2D NMR for KRAS:Ligand Binding.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Production of Isotopically Labeled KRAS4b.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Allosteric Regulation of Switch-II Domain Controls KRAS Oncogenicity.Cancer research · 2023Article
- RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.Science advances · 2023Article
- K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness.Cancers · 2023Article
- Reduced dynamic complexity allows structure elucidation of an excited state of KRASCommunications biology · 2023Article
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Authors and funding
10 authors at 6 institutions in 1 country.
Funding
Abstract
Deregulation of KRAS4b signaling pathway has been implicated in 30% of all cancers. Membrane localization of KRAS4b is an essential step for the initiation of the downstream signaling cascades that guide various cellular mechanisms. KRAS4b plasma membrane (PM) binding is mediated by the insertion of a prenylated moiety that is attached to the terminal carboxy-methylated cysteine, in addition to electrostatic interactions of its positively charged hypervariable region with anionic lipids. Calmodulin (CaM) has been suggested to selectively bind KRAS4b to act as a negative regulator of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway by displacing KRAS4b from the membrane. However, the mechanism by which CaM can recognize and displace KRAS4b from the membrane is not well understood. In this study, we employed biophysical and structural techniques to characterize this mechanism in detail. We show that KRAS4b prenylation is required for binding to CaM and that the hydrophobic pockets of CaM can accommodate the prenylated region of KRAS4b, which might represent a novel CaM-binding motif. Remarkably, prenylated KRAS4b forms a 2:1 stoichiometric complex with CaM in a nucleotide-independent manner. The interaction between prenylated KRAS4b and CaM is enthalpically driven, and electrostatic interactions also contribute to the formation of the complex. The prenylated KRAS4b terminal KSKTKC-farnesylation and carboxy-methylation is sufficient for binding and defines the minimal CaM-binding motif. This is the same region implicated in membrane and phosphodiesterase6-δ binding. Finally, we provide a structure-based docking model by which CaM binds to prenylated KRAS4b. Our data provide new insights into the KRAS4b-CaM interaction and suggest a possible mechanism whereby CaM can regulate KRAS4b membrane localization.
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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.