Exploring the inhibition mechanism of adenylyl cyclase type 5 by n-terminal myristoylated Gαi1

Keulen, Siri C. van; Röthlisberger, Ursula

doi:10.1371/journal.pcbi.1005673

Cited by 19 publications

(61 citation statements)

References 41 publications

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“…The absence of this domain has been shown to reduce the sensitivity of AC5 to Gα i [21]. Nevertheless, the MD simulations performed here and by Van Keulen and Röthlisberger [24] show that Gα i is able to inhibit the activity of AC5 in the absence of the C1b domain. This suggests that the lower inhibition is due to the reduced affinity of Gα i in the absence of C1b, rather than do to a change in the internal mechanism of inhibition.…”

Section: Assumptions and Limitationsmentioning

confidence: 50%

Section: Author Summarymentioning

confidence: 99%

“…AC5 · Gα i + Gα olf ↔ Gα olf · AC5 · Gα i , and AC5 · Gα olf + Gα i ↔ Gα olf · AC5 · Gα i . Previous MD simulation results suggested that upon binding of Gα i to AC5, the Gα olf binding groove adopts a conformation that hinders Gα olf from binding [24], making the first reaction less favourable; however, a stable ternary complex might still be formed via the second route. Allatom MD simulations were employed to investigate the stability of a putative apo ternary complex, Gα olf · AC5 · Gα i , in the absence of ATP, on the μs time scale.…”

Section: Molecular Dynamics Simulations Indicate That the Apo Gα Olf mentioning

confidence: 99%

“…We mention here that Gα olf has no posttranslational modifications to its protein sequence. In contrast, Gα i is considered in its myristoylated form since a non-myristoylated Gα i subunit is known to be unable to form an AC5 · Gα i complex and, therefore, it is not functional [21,24].…”

Section: Molecular Dynamics Simulations Indicate That the Apo Gα Olf mentioning

confidence: 99%

“…1B) [21,23]. So far, we know from molecular dynamics (MD) simulations of the binary complexes that binding of one Gα subunit can produce allosteric effects at the binding site for the other [24,25], raising the speculation that allosteric effects influence ternary complex formation.Resolving the details of AC5 regulation can help to understand whether AC5 acts as a coincidence detector, and hence, whether transient changes in two neuromodulatory signals are necessary for plasticity and learning in the basal ganglia. Here, we take a multiscale modeling approach to address the following question: can the Gα olf · AC5 · Gα i ternary complex form in the AC5 signal transduction network?…”

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confidence: 99%

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Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals

Bruce

Narzi

Trpevski

et al. 2019

Preprint

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Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor in reinforcement learning. Strengthening of the corticostriatal synapses depends on the second messenger cAMP, whose synthesis is catalysed by the enzyme adenylyl cyclase 5 (AC5), which is itself regulated by the stimulatory Gαolf and inhibitory Gαi proteins. AC isoforms have been suggested to act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close in time. However, the mechanism for this is currently unclear, and seems to lie in their diverse regulation patterns. Despite attempts to isolate the ternary complex, it is not known if Gαolf and Gαi can bind to AC5 simultaneously, nor what activity the complex would have. Using protein structure-based molecular dynamics simulations, we show that this complex is stable and inactive. These simulations, along with Brownian dynamics simulations to estimate protein association rates constants, constrain a kinetic model that shows that the presence of this ternary inactive complex is crucial for AC5's ability to detect coincident signals, producing a synergistic increase in cAMP. These results reveal some of the prerequisites for corticostriatal synaptic plasticity, and explain recent experimental data on cAMP concentrations following receptor activation. Moreover, they provide insights into the regulatory mechanisms that control signal processing by different AC isoforms. Author summaryAdenylyl cyclases (ACs) are enzymes that can translate extracellular signals into the intracellular molecule cAMP, which is thus a 2 nd messenger of extracellular events. The brain expresses nine membrane-bound AC variants, and AC5 is the dominant form in the striatum. The striatum is the input stage of the basal ganglia, a brain structure involved in reward learning, i.e. the learning of behaviors that lead to rewarding stimuli (such as food, water, sugar, etc). During reward learning, cAMP production is crucial for strengthening the synapses from cortical neurons onto the striatal principal neurons, and its formation is dependent on several neuromodulatory systems such as dopamine and acetylcholine. It is, however, not understood how AC5 is activated by transient (subsecond) changes in the neuromodulatory signals. Here we combine several computational tools, from molecular dynamics and Brownian dynamics simulations to bioinformatics approaches, to inform and constrain a kinetic model of the AC5-dependent signaling system. We use this model to show how the specific molecular properties of AC5 can detect particular combinations of cooccuring transient changes in the neuromodulatory signals which thus result in a supralinear/synergistic cAMP production. Our results also provide insights into the computational capabilities of the different AC isoforms.Recent experimental data indicates that, during the resting state, much of AC5 in the D1 MSNs could be bound to Gα i due to a tonic level of acetylcholine produced by the tonic activity of the st...

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Section: Assumptions and Limitationsmentioning

confidence: 50%

Section: Author Summarymentioning

confidence: 99%

Section: Molecular Dynamics Simulations Indicate That the Apo Gα Olf mentioning

confidence: 99%

Section: Molecular Dynamics Simulations Indicate That the Apo Gα Olf mentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals

Bruce

Narzi

Trpevski

et al. 2019

Preprint

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Strategies towards Targeting Gαi/s Proteins: Scanning of Protein‐Protein Interaction Sites To Overcome Inaccessibility

Nubbemeyer

Pepanian

George³

et al. 2021

ChemMedChem

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Heterotrimeric G proteins are classified into four subfamilies and play a key role in signal transduction. They transmit extracellular signals to intracellular effectors subsequent to the activation of G protein‐coupled receptors (GPCRs), which are targeted by over 30 % of FDA‐approved drugs. However, addressing G proteins as drug targets represents a compelling alternative, for example, when G proteins act independently of the corresponding GPCRs, or in cases of complex multifunctional diseases, when a large number of different GPCRs are involved. In contrast to Gαq, efforts to target Gαi/s by suitable chemical compounds has not been successful so far. Here, a comprehensive analysis was conducted examining the most important interface regions of Gαi/s with its upstream and downstream interaction partners. By assigning the existing compounds and the performed approaches to the respective interfaces, the druggability of the individual interfaces was ranked to provide perspectives for selective targeting of Gαi/s in the future.

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Multiscale molecular simulations to investigate adenylyl cyclase‐based signaling in the brain

Keulen

Martin

Colizzi

et al. 2022

WIREs Comput Mol Sci

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Adenylyl cyclases (ACs) play a key role in many signaling cascades. ACs catalyze the production of cyclic AMP from ATP and this function is stimulated or inhibited by the binding of their cognate stimulatory or inhibitory Gα subunits, respectively. Here we used simulation tools to uncover the molecular and subcellular mechanisms of AC function, with a focus on the AC5 isoform, extensively studied experimentally. First, quantum mechanical/molecular mechanical free energy simulations were used to investigate the enzymatic reaction and its changes upon point mutations. Next, molecular dynamics simulations were employed to assess the catalytic state in the presence or absence of Gα subunits. This led to the identification of an inactive state of the enzyme

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Exploring the inhibition mechanism of adenylyl cyclase type 5 by n-terminal myristoylated Gαi1

Cited by 19 publications

References 41 publications

Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals

Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals

Strategies towards Targeting Gαi/s Proteins: Scanning of Protein‐Protein Interaction Sites To Overcome Inaccessibility

Multiscale molecular simulations to investigate adenylyl cyclase‐based signaling in the brain

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