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Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior
- Source :
- eLife, eLife, Vol 9 (2020)
- Publication Year :
- 2020
- Publisher :
- eScholarship, University of California, 2020.
-
Abstract
- The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable region side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here, we characterize RAS in live human and mouse cells using single-molecule-tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein’s globular domain. To understand the altered mobility of an oncogenic KRAS4b, we used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism.
- Subjects :
- 0301 basic medicine
Neuroblastoma RAS viral oncogene homolog
Mouse
single molecule tracking
Physics of Living Systems
Molecular dynamics
Mice
physics of living systems
2.1 Biological and endogenous factors
Protein Isoforms
Aetiology
Biology (General)
Cancer Biology
cancer biology
chemistry.chemical_classification
Chemistry
General Neuroscience
General Medicine
RAS diffusion
Cell biology
Amino acid
Membrane
Medicine
Signal transduction
atomistic simulation
Research Article
Human
Gene isoform
QH301-705.5
Science
Molecular Dynamics Simulation
General Biochemistry, Genetics and Molecular Biology
Cell Line
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Protein Domains
Animals
Humans
cancer
HRAS
human
mouse
030102 biochemistry & molecular biology
General Immunology and Microbiology
Cell Membrane
Hypervariable region
030104 developmental biology
Hela Cells
Biochemistry and Cell Biology
HeLa Cells
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- eLife, eLife, Vol 9 (2020)
- Accession number :
- edsair.doi.dedup.....169e46d8abcdbbfc6691fbd11768e154