Toward a molecular mechanism for the interaction of ATP with alpha-synuclein

Kamski-Hennekam, Evelyn Rose; Huang, Jinfeng; Ahmed, Rashik; Melacini, Giuseppe

doi:10.1039/d3sc03612j

Cited by 5 publications

(2 citation statements)

References 51 publications

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“…Chemical shift perturbations (CSPs) can discern local environmental changes around specific nuclei, often associated with conformational transitions . CSP studies of kinases such as Abl, alpha-synuclein, and ERK, alongside segmental labeling in NMR techniques for proteins such as AKT and CDK2, have uncovered distinct mechanisms of allosteric inhibition and activation, offering profound insights that challenge and extend beyond traditional crystallography findings. ,, Building on these studies, we used CSPs, detailed in Materials and Methods Section , to elucidate the differences in conformational changes of CDK2 and CDK4 as they bind to their respective cyclins. By plotting these CSPs along the protein sequence, we can identify the regions or specific residues that are most affected by cyclin binding.…”

Section: Resultsmentioning

confidence: 99%

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

Zhang,

Liu,

Jang

et al. 2024

JACS Au

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Cyclin-dependent kinases (CDKs), particularly CDK4 and CDK2, are crucial for cell cycle progression from the Gap 1 (G1) to the Synthesis (S) phase by phosphorylating targets such as the Retinoblastoma Protein (Rb). CDK4, paired with cyclin-D, operates in the long G1 phase, while CDK2 with cyclin-E, manages the brief G1-to-S transition, enabling DNA replication. Aberrant CDK signaling leads to uncontrolled cell proliferation, which is a hallmark of cancer. Exactly how they accomplish their catalytic phosphorylation actions with distinct efficiencies poses the fundamental, albeit overlooked question. Here we combined available experimental data and modeling of the active complexes to establish their conformational functional landscapes to explain how the two cyclin/CDK complexes differentially populate their catalytically competent states for cell cycle progression. Our premise is that CDK catalytic efficiencies could be more important for cell cycle progression than the cyclin-CDK biochemical binding specificity and that efficiency is likely the prime determinant of cell cycle progression. We observe that CDK4 is more dynamic than CDK2 in the ATP binding site, the regulatory spine, and the interaction with its cyclin partner. The N-terminus of cyclin-D acts as an allosteric regulator of the activation loop and the ATP-binding site in CDK4. Integrated with a suite of experimental data, we suggest that the CDK4 complex is less capable of remaining in the active catalytically competent conformation, and may have a lower catalytic efficiency than CDK2, befitting their cell cycle time scales, and point to critical residues and motifs that drive their differences. Our mechanistic landscape may apply broadly to kinases, and we propose two drug design strategies: (i) allosteric Inhibition by conformational stabilization for targeting allosteric CDK4 regulation by cyclin-D, and (ii) dynamic entropy-optimized targeting which leverages the dynamic, entropic aspects of CDK4 to optimize drug binding efficacy.

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Section: Resultsmentioning

confidence: 99%

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

Zhang,

Liu,

Jang

et al. 2024

JACS Au

View full text Add to dashboard Cite

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“…These ThT-based results are in agreement with our dynamic light scattering (DLS) and negative stain transmission electron microscopy (TEM) data ( Figures 1 E, F and S2 ), with the enhanced β-sheet formation observed by circular dichroism 11 , 12 , 39 , 40 for the E46K mutant compared to wt αS, and with the increased αS aggregation propensity revealed by cross-linking-based sodium dodecyl sulfate polyacrylamide gel electrophoresis, 40 , 41 as well as with Western blot and EM analyses of cultured cells. 9 , 10 , 42 Nevertheless, it is not fully understood how the amplification of αS aggregation can be reconciled with the E46K-induced shift to aggregation-averse closed αS monomers.…”

Section: Introductionmentioning

confidence: 99%

Early-Onset Parkinson Mutation Remodels Monomer–Fibril Interactions to Allosterically Amplify Synuclein’s Amyloid Cascade

Huang,

Ahmed,

Akimoto

et al. 2023

JACS Au

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Alpha synuclein (αS) aggregates are the main component of Lewy bodies (LBs) associated with Parkinson’s disease (PD). A longstanding question about αS and PD pertains to the autosomal dominant E46K αS mutant, which leads to the early onset of PD and LB dementias. The E46K mutation not only promotes αS aggregation but also stabilizes αS monomers in “closed” conformers, which are compact and aggregation-incompetent. Hence, the mechanism of action of the E46K mutation is currently unclear. Here, we show that αS monomers harboring the E46K mutation exhibit more extensive interactions with fibrils compared to those of WT. Such monomer-fibril interactions are sufficient to allosterically drive transitions of αS monomers from closed to open conformations, enabling αS aggregation. We also show that E46K promotes head-to-tail monomer–monomer interactions in early self-association events. This multipronged mechanism provides a new framework to explain how the E46K mutation and possibly other αS variants trigger early-onset PD.

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Amyloid-Driven Allostery

Garcha,

Huang,

Martinez Pomier

et al. 2024

Biophysical Chemistry

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Toward a molecular mechanism for the interaction of ATP with alpha-synuclein

Abstract: The ability of Adenosine Triphosphate (ATP) to modulate protein solubility establishes a critical link between ATP homeostasis and proteinopathies, such as Parkinson’s (PD). The most significant risk factor for PD...

Cited by 5 publications

References 51 publications

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

Early-Onset Parkinson Mutation Remodels Monomer–Fibril Interactions to Allosterically Amplify Synuclein’s Amyloid Cascade

Amyloid-Driven Allostery

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