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

JACS Au, Journal Year: 2024, Volume and Issue: 4(5), P. 1911 - 1927

Published: May 14, 2024

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

Language: Английский

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Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: 4

Published: March 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Language: Английский

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Brain network and energy imbalance in Parkinson’s disease: linking ATP reduction and α-synuclein pathology

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 22, 2025

Parkinson’s disease (PD) involves the disruption of brain energy homeostasis. This encompasses broad-impact factors such as mitochondrial dysfunction, impaired glycolysis, and other metabolic disturbances, like disruptions in pentose phosphate pathway purine metabolism. Cortical hubs, which are highly connected regions essential for coordinating multiple functions, require significant due to their dense synaptic activity long-range connections. Deficits ATP production PD can severely impair these hubs. The imbalance also affects subcortical regions, including massive axonal arbors striatum substantia nigra pars compacta neurons, high demand. decline may result α -synuclein accumulation, autophagy-lysosomal system impairment, neuronal network breakdown accelerated neurodegeneration. We propose an “ATP Supply–Demand Mismatch Model” help explain pathogenesis PD. model emphasizes how deficits drive pathological protein aggregation, autophagy, degeneration key networks, contributing both motor non-motor symptoms.

Language: Английский

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A nanozipper structured efficient FRET probe for ratiometric detection of ATP based on target-induced cycling amplification

Sensors and Actuators B Chemical, Journal Year: 2023, Volume and Issue: 401, P. 134890 - 134890

Published: Nov. 3, 2023

Language: Английский

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

JACS Au, Journal Year: 2023, Volume and Issue: 3(12), P. 3485 - 3493

Published: Dec. 13, 2023

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 autosomal dominant E46K mutant, which leads early onset LB dementias. The mutation not only promotes aggregation but also stabilizes monomers in "closed" conformers, compact aggregation-incompetent. Hence, mechanism action is currently unclear. Here, we show that harboring exhibit more extensive interactions fibrils compared those WT. Such monomer-fibril sufficient allosterically drive transitions from closed open conformations, enabling aggregation. We head-to-tail monomer-monomer self-association events. This multipronged provides a new framework explain how possibly other variants trigger early-onset PD.

Language: Английский

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In the Beginning: Let Hydration Be Coded in Proteins for Manifestation and Modulation by Salts and Adenosine Triphosphate

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12817 - 12817

Published: Nov. 28, 2024

Water exists in the beginning and hydrates all matter. Life emerged water, requiring three essential components compartmentalized spaces: (1) universal energy sources driving biochemical reactions processes, (2) molecules that store, encode, transmit information, (3) functional players carrying out biological activities structural organization. Phosphorus has been selected to create adenosine triphosphate (ATP) as currency, nucleic acids for genetic information storage transmission, phospholipids cellular compartmentalization. Meanwhile, proteins composed of 20 α-amino have evolved into extremely diverse three-dimensional forms, including folded domains, intrinsically disordered regions (IDRs), membrane-bound fulfill roles. This review examines several unique findings: insoluble proteins, membrane can become solubilized unsalted while cytosolic acquire membrane-inserting capacity; Hofmeister salts affect protein stability by targeting hydration; ATP biphasically modulates liquid-liquid phase separation (LLPS) IDRs; (4) antagonizes crowding-induced destabilization; (5) triphosphates highest efficiency inducing folding. These findings imply following: hydration might be encoded sequences, central manifestation modulation structures, dynamics, functionalities; phosphate anions a capacity enhancing μs-ms likely through ionic state exchanges shell, underpinning ATP, polyphosphate, molecular chaperones folding; linking with adenosine, acquired spacetime-specifically release modulate hydration, thus possessing myriad energy-dependent -independent functions. In light success AlphaFolds accurately predicting structures neural networks store distributed patterns across nodes, fundamental question arises: Could also handle similarly but more intricate coding, topological architectures, spacetime-specific supply membrane-compartmentalized aqueous environments?

Language: Английский

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Amyloid-Driven Allostery

Biophysical Chemistry, Journal Year: 2024, Volume and Issue: 315, P. 107320 - 107320

Published: Aug. 30, 2024

The fields of allostery and amyloid-related pathologies, such as Parkinson's disease (PD), have been extensively explored individually, but less is known about how amyloids control allostery. Recent advancements revealed that can drive allosteric effects in both intrinsically disordered proteins, alpha-synuclein (αS), multi-domain signaling protein kinase A (PKA). Amyloid-driven plays a central role explaining the mechanisms gain-of-pathological-function mutations αS (e.g. E46K, which causes early PD onset) loss-of-physiological-function PKA A211D, predisposes to tumors). This review highlights disease-related they cause exposure amyloidogenic regions, leading are either toxic or aberrant signaling. We also discuss multiple potential modulators these effects, MgATP substrates, opening future opportunities improve current pharmacological interventions against PKA-related pathologies. Overall, we show amyloid-driven models useful explain underlying mutations.

Language: Английский

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