ArticleChemical science2021
Oncogenic KRAS G12D mutation promotes dimerization through a second, phosphatidylserine-dependent interface: a model for KRAS oligomerization.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Structural and Energetic Determinants of Monobody Recognition of Oncogenic KRAS Variants.bioRxiv : the preprint server for biology · 2026Article
- KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.Journal of lipid research · 2026Article
- Phosphatidylinositol 4,5-bisphosphate mediates Arl4D self-interaction to promote Pak1 signaling.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The Nanodisc System for Investigating Protein-Lipid Interactions.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Targeting KRAS G12D: Advances in Inhibitor Design.Thoracic cancer · 2025Review
- Article
- Kinetic analysis of catalytic activity of G-quadruplex/hemin DNAzyme with flanking adenine nucleotides.Scientific reports · 2025Article
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- Site-directed antibodies targeting driver mutations of the KRAS protein.New biotechnology · 2025Article
- Effector Binding Sequentially Alters KRAS Dimerization on the Membrane: New Insights Into RAS-Mediated RAF Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
- Membrane-Driven Dimerization of the Peripheral Membrane Protein KRAS: Implications for Downstream Signaling.International journal of molecular sciences · 2024Review
- Probing RAS Function Using Monobody and NanoBiT Technologies.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Structural insights into the complex of oncogenic KRas4BLife science alliance · 2024Article
- Crystal Packing Reveals a Potential Autoinhibited KRAS Dimer Interface and a Strategy for Small-Molecule Inhibition of RAS Signaling.Biochemistry · 2023Article
- 3DVizSNP: a tool for rapidly visualizing missense mutations identified in high throughput experiments in iCn3D.BMC bioinformatics · 2023Article
- Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors.Molecules (Basel, Switzerland) · 2023Review
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- Exploring CRD mobility during RAS/RAF engagement at the membrane.Biophysical journal · 2022Article
- Nanoscopic Spatial Association between Ras and Phosphatidylserine on the Cell Membrane Studied with Multicolor Super Resolution Microscopy.Biomolecules · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
KRAS forms transient dimers and higher-order multimers (nanoclusters) on the plasma membrane, which drive MAPK signaling and cell proliferation. KRAS is a frequently mutated oncogene, and while it is well known that the most prevalent mutation, G12D, impairs GTP hydrolysis, thereby increasing KRAS activation, G12D has also been shown to enhance nanoclustering. Elucidating structures of dynamic KRAS assemblies on a membrane has been challenging, thus we have refined our NMR approach that uses nanodiscs to study KRAS associated with membranes. We incorporated paramagnetic relaxation enhancement (PRE) titrations and interface mutagenesis, which revealed that, in addition to the symmetric 'α-α' dimerization interface shared with wild-type KRAS, the G12D mutant also self-associates through an asymmetric 'α-β' interface. The 'α-β' association is dependent on the presence of phosphatidylserine lipids, consistent with previous reports that this lipid promotes KRAS self-assembly on the plasma membrane in cells. Experiments using engineered mutants to spoil each interface, together with PRE probes attached to the membrane or free in solvent, suggest that dimerization through the primary 'α-α' interface releases β interfaces from the membrane promoting formation of the secondary 'α-β' interaction, potentially initiating nanoclustering. In addition, the small molecule BI-2852 binds at a β-β interface, stabilizing a new dimer configuration that outcompetes native dimerization and blocks the effector-binding site. Our data indicate that KRAS self-association involves a delicately balanced conformational equilibrium between transient states, which is sensitive to disease-associated mutation and small molecule inhibitors. The methods developed here are applicable to biologically important transient interactions involving other membrane-associated proteins.
Identifiers
What OpenQuestion holds
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.