ArticlePhysical chemistry chemical physics : PCCP2017
The dynamic mechanism of RASSF5 and MST kinase activation by Ras.
Article in Physical chemistry chemical physics : PCCP, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- MST1/2 in inflammation and immunity.Cell adhesion & migration · 2023Review
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Regulation of MST complexes and activity via SARAH domain modifications.Biochemical Society transactions · 2021Review
- The mechanism of activation of monomeric B-Raf V600E.Computational and structural biotechnology journal · 2021Article
- In silico analysis predicting effects of deleterious SNPs of human RASSF5 gene on its structure and functions.Scientific reports · 2020Article
- SOS1 interacts with Grb2 through regions that induce closed nSH3 conformations.The Journal of chemical physics · 2020Article
- High-Affinity Interactions of the nSH3/cSH3 Domains of Grb2 with the C-Terminal Proline-Rich Domain of SOS1.Journal of the American Chemical Society · 2020Article
- The quaternary assembly of KRas4B with Raf-1 at the membrane.Computational and structural biotechnology journal · 2020Article
- The structural basis for Ras activation of PI3Kα lipid kinase.Physical chemistry chemical physics : PCCP · 2019Article
- New type of interaction between the SARAH domain of the tumour suppressor RASSF1A and its mitotic kinase Aurora A.Scientific reports · 2019Article
- Does Ras Activate Raf and PI3K Allosterically?Frontiers in oncology · 2019Review
- Autoinhibition in Ras effectors Raf, PI3Kα, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention.Biophysical reviews · 2018Review
- Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.Biophysical journal · 2018Article
- PDEδ Binding to Ras Isoforms Provides a Route to Proper Membrane Localization.The journal of physical chemistry. B · 2017Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway. Structurally, activation involves RASSF5 and MST1/2 swapping their SARAH domains to form a SARAH heterodimer. This exposes the MST1/2 kinase domain which homodimerizes, leading to trans-autophosphorylation. The SARAH-SARAH interaction shifts RASSF5 away from its autoinhibited state and relieves MST1/2 autoinhibition. Separate crystal structures are available for the RA (Ras association) domain and SARAH dimer, where SARAH is a long straight α-helix. Using all-atom molecular dynamics simulations, we modeled the RASSF5 RA with a covalently connected SARAH to elucidate the dynamic mechanism of how SARAH mediates between autoinhibition and Ras triggered-activation. Our results show that in inactive RASSF5 the RA domain retains SARAH, yielding a self-associated conformation in which SARAH is in a kinked α-helical motif that increases the binding interface. When RASSF5 binds K-Ras4B-GTP, the equilibrium shifts toward SARAH's interacting with MST. Since the RA/SARAH affinity is relatively low, whereas that of the SARAH heterodimer is in the nM range, we suggest that RASSF5 exerts its tumor suppressor action through competition with other Ras effectors for Ras effector binding site, as well as coincidentally its recruitment to the membrane to help MST activation. Thus, SARAH plays a key role in RASSF5's tumor suppression action by linking the two major pathways in tumor cell proliferation: Ras and the MAPK (tumor cell proliferation-promoting) pathway, and the Hippo (tumor cell proliferation-suppressing) pathway.
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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.