AI Article Synopsis
- Ca-stimulated translocation of cytosolic phospholipase Aα (cPLAα) to the Golgi is crucial for producing arachidonic acid, a key component in inflammation-related compounds.
- The study provides a detailed structure of the cPLAα C2-domain, revealing how calcium ions and a specific phospholipid (DHPC) bind to it.
- Key amino acids, Tyr96 and Asn65, were identified as essential for the C2-domain's preference for certain lipids, which enhances understanding of how cPLAα functions in lipid interactions.
Article Abstract
Ca-stimulated translocation of cytosolic phospholipase Aα (cPLAα) to the Golgi induces arachidonic acid production, the rate-limiting step in pro-inflammatory eicosanoid synthesis. Structural insights into the cPLAα preference for phosphatidylcholine (PC)-enriched membranes have remained elusive. Here, we report the structure of the cPLAα C2-domain (at 2.2 Å resolution), which contains bound 1,2-dihexanoyl--glycero-3-phosphocholine (DHPC) and Ca ions. Two Ca are complexed at previously reported locations in the lipid-free C2-domain. One of these Caions, along with a third Ca, bridges the C2-domain to the DHPC phosphate group, which also interacts with Asn65. Tyr96 plays a key role in lipid headgroup recognition via cation-π interaction with the PC trimethylammonium group. Mutagenesis analyses confirm that Tyr96 and Asn65 function in PC binding selectivity by the C2-domain and in the regulation of cPLAα activity. The DHPC-binding mode of the cPLAα C2-domain, which differs from phosphatidylserine or phosphatidylinositol 4,5-bisphosphate binding by other C2-domains, expands and deepens knowledge of the lipid-binding mechanisms mediated by C2-domains.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550875 | PMC |
| http://dx.doi.org/10.7554/eLife.44760 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Elucidating on the quaternary structure of viper venom phospholipase A enzymes in aqueous solution.
Biochimie
January 2025
LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal. Electronic address:
This study focuses on the quaternary structure of the viper-secreted phospholipase A (PLA), a central toxin in viper envenomation. PLA enzymes catalyze the hydrolysis of the sn-2 ester bond of membrane phospholipids. Small-molecule inhibitors that act as snakebite antidotes, such as varespladib, are currently in clinical trials.
View Article and Find Full Text PDFAnthranilic Acid-G-Protein Coupled Receptor109A-Cytosolic Phospholipase A2-Myelin-Cognition Cascade: A New Target for the Treatment/Prevention of Cognitive Impairment in Schizophrenia, Dementia, and Aging.
Int J Mol Sci
December 2024
Department of Psychiatry, Tufts University School of Medicine, Boston, MA 02111, USA.
Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer's dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-β in neuritic plaques.
View Article and Find Full Text PDFLipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors.
J Immunother Cancer
January 2025
Qingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong, People's Republic of China
Background: Tumor cells can drive the senescence of effector T cells by unbalancing their lipid metabolism, thereby limiting adoptive T cell therapy and contributing to tumor immune evasion. Our objective is to provide a feasible strategy for enhancing T cell treatment efficacy against solid tumors.
Methods: In this study, liposomal arachidonyl trifluoromethyl ketone (ATK) was anchored onto the adoptive T cell surface via bioorthogonal reactions, aiming to specifically inhibit the group IVA cytosolic phospholipase Aα (cPLAα), a key enzyme facilitating phospholipid metabolism and senescent state of T cells.
Cytosolic phospholipase A2 in infiltrating monocyte derived macrophages does not impair recovery after spinal cord injury in female mice.
Sci Rep
January 2025
Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
Spinal cord injury (SCI) leads to permanent motor and sensory loss that is exacerbated by intraspinal inflammation and persists months to years after injury. After SCI, monocyte-derived macrophages (MDMs) infiltrate the lesion to aid in myelin-rich debris clearance. During debris clearance, MDMs adopt a proinflammatory phenotype that exacerbates neurodegeneration and hinders recovery.
View Article and Find Full Text PDFNext generation thiazolyl ketone inhibitors of cytosolic phospholipase A α for targeted cancer therapy.
Nat Commun
January 2025
Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway.
Eicosanoids are key players in inflammatory diseases and cancer. Targeting their production by inhibiting Group IVA cytosolic phospholipase A (cPLAα) offers a promising approach for cancer therapy. In this study, we synthesize a second generation of thiazolyl ketone inhibitors of cPLAα starting with compound GK470 (AVX235) and test their in vitro and cellular activities.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!