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Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.

ABSTRACT: Membrane-anchored Ras family proteins are activated by guanine nucleotide exchange factors such as SOS1. The CDC25 domain of SOS1 catalyzes GDP-to-GTP exchange, thereby activating Ras. Here, we aim to decipher the activation mechanism of KRas4B, a significantly mutated oncogene. We perform large-scale molecular dynamics simulations on 12 SOS1 systems, scrutinizing each step in two possible KRas4B activation cycles, fast and slow. To activate KRas4B at the CDC25 catalytic site, the allosteric site in the Ras exchanger motif (REM) domain of SOS1 needs to recruit a (nucleotide-bound) KRas4B molecule. Our simulations indicate that KRas4B-GTP interacts with the REM allosteric site more strongly than with the CDC25 catalytic site, consistent with its allosteric role in the GDP-to-GTP exchange. In the fast cycle, the allosteric KRas4B-GTP induces conformational change at the catalytic site. The conformational change facilitates loading KRas4B-GDP at the catalytic site and opening the KRas4B nucleotide-binding site for GDP release and GTP binding. GTP binding reduces the affinity of KRas4B-GTP to the CDC25 catalytic site, resulting in its release. By contrast, in the slow cycle, KRas4B-GDP binds at the allosteric REM site. The limited, altered conformational change that it induces prevents the exact alignments of switch I and II of KRas4B. The increasing binding strength at both binding sites due to interactions of regions other than switch I and II retards GDP release from the catalytic KRas4B, thus KRas4B activation. The accelerated activation cycle supports a positive feedback loop with allosteric signals communicating between the two Ras molecules and is the predominant, native function of SOS. SOS1 activation details may help drug discovery to inhibit Ras activation.

SUBMITTER: Liao TJ

PROVIDER: S-EPMC6103739 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.

Liao Tsung-Jen TJ Jang Hyunbum H Fushman David D Nussinov Ruth R

Biophysical journal 20180724 4

Membrane-anchored Ras family proteins are activated by guanine nucleotide exchange factors such as SOS1. The CDC25 domain of SOS1 catalyzes GDP-to-GTP exchange, thereby activating Ras. Here, we aim to decipher the activation mechanism of KRas4B, a significantly mutated oncogene. We perform large-scale molecular dynamics simulations on 12 SOS1 systems, scrutinizing each step in two possible KRas4B activation cycles, fast and slow. To activate KRas4B at the CDC25 catalytic site, the allosteric sit ...[more]

PMID: 30097175

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Project description:The contractile properties of fast-twitch and slow-twitch skeletal muscles are primarily determined by the myosin isoform content and modulated by a variety of sarcomere proteins. X-ray diffraction studies of regulatory mechanisms in muscle contraction have focused predominately on fast- or mixed-fibre muscle with slow muscle being much less studied. Here, we used time-resolved X-ray diffraction to investigate the dynamic behaviour of the myofilament proteins in relatively pure slow-twitch-fibre rat soleus (SOL) and pure fast-twitch-fibre rat extensor digitorum longus (EDL) muscle during twitch and tetanic contractions at optimal length. During twitch contractions the diffraction signatures indicating a transition in the myosin heads from ordered OFF states, where heads are held close to the thick filament backbone, to disordered ON states, where heads are free to bind to thin filaments, were found in EDL and not in SOL muscle. During tetanic contraction, changes in the disposition of myosin heads as active tension develops is a quasi-stepwise process in EDL muscle whereas in SOL muscle this relationship appears to be linear. The observed reduced extensibility of the thick filaments in SOL muscle as compared to EDL muscles indicates a molecular basis for this behaviour. These data indicate that for the EDL, thick filament activation is a cooperative strain-induced mechano-sensing mechanism, whereas for the SOL, thick filament activation has a more graded response. These different approaches to thick filament regulation in fast- and slow-twitch muscles may be adaptations for short-duration, strong contractions versus sustained, finely controlled contractions, respectively. KEY POINTS: Fast-twitch muscle and slow-twitch muscle are optimized for strong, short-duration contractions and for tonic postural activity, respectively. Structural events (OFF to ON transitions) in the myosin-containing thick filaments in fast muscle help determine the timing and strength of contractions, but these have not been studied in slow-twitch muscle. The X-ray diffraction signatures of structural OFF to ON transitions are different in fast extensor digitorum longus (EDL) and slow soleus (SOL) muscle, being completely absent during twitches in soleus muscle and blunted during tetanic contractions SOL as compared to EDL Quasi-stepwise thick filament structural OFF to ON transitions in fast twitch muscle may be an adaptation for rapid, ballistic movements, whereas more graded OFF to ON structural transitions in slow-twitch muscle may be an adaptation for slower, finer motions.

Dataset Information

Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.

Publications

Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.

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