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Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
Proc Natl Acad Sci U S A
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Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
ClpXP is a two-component mitochondrial matrix protease. The caseinolytic mitochondrial matrix peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of the caseinolytic protease P (ClpP) for proteolysis. ClpXP degrades damaged respiratory chain proteins and is necessary for cancer cell survival.
View Article and Find Full Text PDFSmall Molecule Modulators of AMP-Activated Protein Kinase (AMPK) Activity and Their Potential in Cancer Therapy.
J Med Chem
January 2025
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States.
AMP-activated protein kinase (AMPK) is a central mediator of cellular metabolism and is activated in direct response to low ATP levels. Activated AMPK inhibits anabolic pathways and promotes catabolic activities that generate ATP through the phosphorylation of multiple target substrates. AMPK is a therapeutic target for activation in several chronic metabolic diseases, and there is increasing interest in targeting AMPK activity in cancer where it can act as a tumor suppressor or conversely it can support cancer cell survival.
View Article and Find Full Text PDFEpigenetic modulation rescues neurodevelopmental deficits in Syngap1 mice.
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Molecular Biology and Genetics Unit, Transcription and Disease Laboratory, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India.
SYNGAP1 is a Ras GTPase-activating protein that plays a crucial role during brain development and in synaptic plasticity. Sporadic heterozygous mutations in SYNGAP1 affect social and emotional behaviour observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape of SYNGAP1 mutation-mediated intellectual disability is unexplored.
View Article and Find Full Text PDFPP2A Attenuates Thoracic Aneurysm and Dissection in Mouse Models of Marfan Syndrome.
Hypertension
January 2025
Cardiology Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA. (X.Z., Q.X., A.V., Z.L.).
Background: Recent studies show that hyperactivation of mTOR (mammalian target of rapamycin) signaling plays a causal role in the development of thoracic aortic aneurysm and dissection. Modulation of PP2A (protein phosphatase 2A) activity has been shown to be of significant therapeutic value. In light of the effects that PP2A can exert on the mTOR pathway, we hypothesized that PP2A activation by small-molecule activators of PP2A could mitigate AA progression in Marfan syndrome (MFS).
View Article and Find Full Text PDFFunctionally active modulators targeting the LRRK2 WD40 repeat domain identified by FRASE-bot in CACHE Challenge #1.
Chem Sci
January 2025
University of Missouri - Columbia, Department of Chemistry USA
Critical Assessment of Computational Hit-Finding Experiments (CACHE) Challenges emerged as real-life stress tests for computational hit-finding strategies. In CACHE Challenge #1, 23 participants contributed their original workflows to identify small-molecule ligands for the WD40 repeat (WDR) of LRRK2, a promising Parkinson's target. We applied the FRASE-based hit-finding robot (FRASE-bot), a platform for interaction-based screening allowing a drastic reduction of the explorable chemical space and a concurrent detection of putative ligand-binding sites.
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