Molecular mechanisms of asymmetric RAF dimer activation

Jambrina, Pablo G.; Bohuszewicz, Olga; Buchete, Nicolae‐Viorel; Kölch, Walter; Rosta, Edina

doi:10.1042/bst20140025

Cited by 29 publications

(27 citation statements)

References 48 publications

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“…Total atom numbers for each system including water molecules are reported in Table 1. Systems were prepared for MD simulation as described in our previous papers using also similar NPT MD studies [38–40] of larger amyloid peptides such as Alzheimer’s amyloid-beta (Aβ, [41–43]) or human amylin (hIAPP, [44]).…”

Section: Methodsmentioning

confidence: 99%

Conformational dynamics and aggregation behavior of piezoelectric diphenylalanine peptides in an external electric field

Kelly

Northey

Ryan

et al. 2015

Biophysical Chemistry

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Aromatic peptides such as diphenylalanine (FF) have the characteristic capacity to self-assemble into ordered nanostructures such as peptide nanotubes, which are biocompatible, thermally and chemically stable, and have strong piezoelectric activity and high mechanical strength. The physical properties of FF aggregates open up a variety of potential biomedical applications. Electric fields are commonly applied to align FF nanotubes, yet little is known about the effect of the electric field on the assembly process. Using all-atom molecular dynamics with explicit water molecules, we probe the conformational dynamics of individual, solvated FF molecules with both charged and neutral ends, to account for different possible pH conditions. With charged ends, the FF molecules show more complex dynamics, experiencing three main conformational states (cis, trans and extended). We first examine the structural response of FF monomers to the application of a constant external electric field over a range of intensities. We also probe the aggregation mechanism of FF peptides, both with and without an externally applied electric field, and find that the presence of even relatively weak fields can accelerate the formation of ordered FF aggregates, primarily by facilitating the alignment of individual molecular dipole moments. The correlation between the strength of the external electric field and the local dipolar interactions is modulated both by the conformational response of individual FF peptides (e.g. backbone stretching, hydrogen bonds and relative alignment of aromatic sidechains) and by the response of neighboring FF and water molecules. These field-dependent observations may facilitate future studies on the controlled formation of nano-structured aggregates of piezoelectric peptides and the understanding of their specific electromechanical properties.

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Section: Methodsmentioning

confidence: 99%

Conformational dynamics and aggregation behavior of piezoelectric diphenylalanine peptides in an external electric field

Kelly

Northey

Ryan

et al. 2015

Biophysical Chemistry

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“…Intriguingly, these salt bridges are primarily interprotomer salt bridges, which are formed between the NtA motif and positive residues located either upstream of the NtA motif or at the C‐terminal end of the αC‐helix, the orientation of which plays an important role in kinase activation 12a, 13…”

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confidence: 99%

Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

et al. 2015

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RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N‐terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC‐helix and charged residues upstream of the NtA motif. Additionally, we show that the R‐spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure‐based mechanism for the auto‐transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization‐related drug resistance.

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“…The proximity of the N region to the dimer interface has been noted (20,66,67). Molecular dynamic simulations have suggested that the phosphorylation of the N region expands this dimer interface, in part by enhancing potential electrostatic interactions between the N region and the opposite RKTR motif that lies within the ␣C helix of the opposite Raf monomer (68,69). That study predicted structural changes within the Raf dimer.…”

Section: Discussionmentioning

confidence: 83%

Phosphorylation of the C-Raf N Region Promotes Raf Dimerization

Takahashi

Dillon

et al. 2017

Molecular and Cellular Biology

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Activation of Raf kinases by the small GTPase Ras requires two major sets of phosphorylations. One set lies within the activation loop and the other lies within the N-terminal acidic region (N-region). In the most abundant isoform of Raf, C-Raf, N-region phosphorylations occur on serine 338 (S338) and tyrosine 341 (Y341), and are thought to provide allosteric activation of the Raf dimer. We show that the phosphorylation of these N-region sites does not require C-Raf dimerization, but rather, they precede dimerization. One of these phosphorylations (phospho-Y341) is required for C-Raf dimerization and this action can be replicated by phosphomimetic mutants both and The role of phosphorylation of Y341 in promoting Raf dimerization is distinct from its well-known function to facilitate S338 phosphorylation.In Ras-mutant pancreatic cancer cell lines, phosphorylation and dimerization of C-Raf is basally elevated. Dimerization is thought to contribute to their elevated growth rate through their activation of the MAP kinase (ERK) signaling cascade. Blocking tyrosine phosphorylation of C-Raf with Src family inhibitors blocks the growth, basal dimerization, and ERK activation in these cells. We suggest that the kinases mediating C-Raf Y341 phosphorylation are potential candidate drug targets in selected Ras-dependent cancers.

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Molecular mechanisms of asymmetric RAF dimer activation

Cited by 29 publications

References 48 publications

Conformational dynamics and aggregation behavior of piezoelectric diphenylalanine peptides in an external electric field

Conformational dynamics and aggregation behavior of piezoelectric diphenylalanine peptides in an external electric field

Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

Phosphorylation of the C-Raf N Region Promotes Raf Dimerization

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