ArticleProceedings of the National Academy of Sciences of the United States of America2015
Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers.
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Who cites it
142 citing papers in PubMed, 226 citations in OpenAlex.
- KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.Journal of lipid research · 2026Article
- Binding orientation of weakly associating membrane peripheral proteins via membrane paramagnetic relaxation enhancement NMR.Communications chemistry · 2026Article
- Rheb membrane orientation dynamics and functional consequences elucidated by molecular simulations, single-molecule-FRET and signaling assays.bioRxiv : the preprint server for biology · 2026Article
- Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding.Nature communications · 2026Article
- The Nanodisc System for Investigating Protein-Lipid Interactions.Methods in molecular biology (Clifton, N.J.) · 2026Review
- DA-Raf synergistically binds to the plasma membrane and Ras to suppress ERK signaling.Life science alliance · 2025Article
- A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.Molecular oncology · 2025Article
- Sequence Determinants of Allosteric Back-to-front Control of the Arf Nucleotide Switch.Journal of molecular biology · 2025Article
- Silicon-rhodamine-enabled identification for near-infrared light controlled proximity labeling in vitro and in vivo.Nature communications · 2025Article
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Distinct association of HRAS and KRAS with MnMagnetic resonance letters · 2025Article
- The small GTPase MRAS is a broken switch.Nature communications · 2025Article
- Motif-guided identification of KRAS-interacting proteins.BMC biology · 2024Article
- From disorder comes function: Regulation of small GTPase function by intrinsically disordered lipidated membrane anchor.Current opinion in structural biology · 2024Review
- KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways.Cells · 2024Review
- Reconstitution and characterization of BRAF in complex with 14-3-3 and KRAS4B on nanodiscs.Protein science : a publication of the Protein Society · 2024Article
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
- Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.Biophysical journal · 2024Article
82 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
K-RAS4B (Kirsten rat sarcoma viral oncogene homolog 4B) is a prenylated, membrane-associated GTPase protein that is a critical switch for the propagation of growth factor signaling pathways to diverse effector proteins, including rapidly accelerated fibrosarcoma (RAF) kinases and RAS-related protein guanine nucleotide dissociation stimulator (RALGDS) proteins. Gain-of-function KRAS mutations occur frequently in human cancers and predict poor clinical outcome, whereas germ-line mutations are associated with developmental syndromes. However, it is not known how these mutations affect K-RAS association with biological membranes or whether this impacts signal transduction. Here, we used solution NMR studies of K-RAS4B tethered to nanodiscs to investigate lipid bilayer-anchored K-RAS4B and its interactions with effector protein RAS-binding domains (RBDs). Unexpectedly, we found that the effector-binding region of activated K-RAS4B is occluded by interaction with the membrane in one of the NMR-observable, and thus highly populated, conformational states. Binding of the RAF isoform ARAF and RALGDS RBDs induced marked reorientation of K-RAS4B from the occluded state to RBD-specific effector-bound states. Importantly, we found that two Noonan syndrome-associated mutations, K5N and D153V, which do not affect the GTPase cycle, relieve the occluded orientation by directly altering the electrostatics of two membrane interaction surfaces. Similarly, the most frequent KRAS oncogenic mutation G12D also drives K-RAS4B toward an exposed configuration. Further, the D153V and G12D mutations increase the rate of association of ARAF-RBD with lipid bilayer-tethered K-RAS4B. We revealed a mechanism of K-RAS4B autoinhibition by membrane sequestration of its effector-binding site, which can be disrupted by disease-associated mutations. Stabilizing the autoinhibitory interactions between K-RAS4B and the membrane could be an attractive target for anticancer drug discovery.
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