Targeting cuproplasia and cuproptosis in cancer

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(5), P. 370 - 388

Published: March 14, 2024

Language: Английский

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Cuproptosis: molecular mechanisms, cancer prognosis, and therapeutic applications

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 22, 2025

Cuproptosis differs from other forms of cell death, such as apoptosis, necroptosis, and ferroptosis, in its unique molecular mechanisms signaling pathways. In this review, we delve into the cellular metabolic pathways copper, highlighting role copper biomolecule synthesis, mitochondrial respiration, antioxidant defense. Furthermore, elucidate relationship between cuproptosis-related genes (CRGs) cancer prognosis, analyzing their expression patterns across various tumor types impact on patient outcomes. Our review also uncovers potential therapeutic applications chelators, ionophores, copper-based nanomaterials oncology. addition, discuss emerging cuproptosis remodeling microenvironment, enhancing immune infiltration, converting "cold tumors" "hot that respond better to immunotherapy. short, underscores pivotal importance biology highlights translational a novel target.

Language: Английский

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P-type ATPases: Many more enigmas left to solve

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(11), P. 105352 - 105352

Published: Oct. 12, 2023

P-type ATPases constitute a large ancient super-family of primary active pumps that have diverse substrate specificities ranging from H+ to phospholipids. The significance these enzymes in biology cannot be overstated. They are structurally related, and their catalytic cycles alternate between high- low-affinity conformations induced by phosphorylation dephosphorylation conserved aspartate residue. In the year 1988, all sequences available then were analyzed five major families, P1 P5, identified. Since then, body knowledge has accumulated concerning structure, function, physiological roles members but only one additional family, P6 ATPases, been However, much is still left learned. For each family few remaining enigmas presented, with intention they will stimulate interest continued research field. review no way comprehensive merely presents personal views focus on evolution.

Language: Английский

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Cuproptosis and Cu: a new paradigm in cellular death and their role in non-cancerous diseases

APOPTOSIS, Journal Year: 2024, Volume and Issue: 29(9-10), P. 1330 - 1360

Published: July 16, 2024

Language: Английский

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Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 27, 2024

Abstract Copper transporting P-type (P 1B-1 -) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P -ATPases remains poorly understood. In particular, role intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations a -ATPase combined to reveal that in many eukaryotes MBD immediately prior ATPase core, −1 , serves structural role, remodeling ion-uptake region. contrast, −2 likely assists copper delivery core. Invariant Tyr, Asn Ser residues transmembrane domain assist positioning sulfur-providing copper-binding amino acids, allowing uptake, release. As such, our findings unify previously conflicting data on transport regulation -ATPases. The results critical fundamental understanding homeostasis comprehension bases -disorders ongoing clinical trials.

Language: Английский

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MAMMALIAN COPPER HOMEOSTASIS: PHYSIOLOGIC ROLES AND MOLECULAR MECHANISMS

Physiological Reviews, Journal Year: 2024, Volume and Issue: 105(1), P. 441 - 491

Published: Aug. 22, 2024

In the past decade, evidence for numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries Cu involvement cell signaling, autophagy, motility, differentiation, and regulated death (cuproptosis) have markedly extended list already known functions Cu, such as a cofactor essential metabolic enzymes, protein structural component, regulator trafficking. Novel unexpected transporting proteins enzymes been identified, new disorders homeostasis described. Significant progress made mechanistic studies two classic metabolism, Menkes disease Wilson’s disease, which paved way novel approaches to their treatment. discovery cuproptosis role metastatic growth increased interest targeting homeostatic pathways treat cancer. this review, we summarize established concepts field discuss how decade expand modify these concepts. brain metabolism functional speciation recently discovered attracted significant attention are highlighted review.

Language: Английский

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Structure and mechanism of the human copper transporting ATPases: Fitting the pieces into a moving puzzle

Biochimica et Biophysica Acta (BBA) - Biomembranes, Journal Year: 2024, Volume and Issue: 1866(4), P. 184306 - 184306

Published: Feb. 24, 2024

Human copper transporters ATP7B and ATP7A deliver to biosynthetic pathways maintain homeostasis in the cell. These enzymes combine several challenges for structural biology because they are large low abundance membrane proteins with many highly mobile domains long disordered loops. No method has yet succeeded solving structure of complete fully functional protein. Still, X-ray crystallography, Cryo-EM NMR helped piece together a based model enzyme activity regulation by copper. We review structures an emphasis on mechanistic insights into unique aspects transport function human ATPases that have emerged from more than twenty years research.

Language: Английский

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Genome-Wide Identification and Expression Profiling of Heavy Metal ATPase (HMA) Genes in Peanut: Potential Roles in Heavy Metal Transport

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(1), P. 613 - 613

Published: Jan. 3, 2024

The heavy metal ATPase (HMA) family belongs to the P-type superfamily and plays an essential role in regulation of homeostasis plants. However, gene has not been fully investigated peanut. Here, a genome-wide identification bioinformatics analysis was performed on AhHMA genes peanut, expression 12 response Cu, Zn, Cd evaluated two peanut cultivars (Silihong Fenghua 1) differing accumulation. A total 21 were identified genome, including ten paralogous pairs derived from whole-genome duplication, additional resulting tandem duplication. proteins could be divided into six groups (I-VI), belonging clades (Zn/Co/Cd/Pb-ATPases Cu/Ag-ATPases). Most within same clade or group generally have similar structure. significant divergence exists exon/intron organization even between duplicated pairs. RNA-seq data showed that most are preferentially expressed roots, shoots, reproductive tissues. qRT-PCR results revealed AhHMA1.1/1.2, AhHMA3.1/3.2, AhHMA7.1/7.4, AhHMA8.1 might involved Zn transport plants, while AhHMA3.2 AhHMA7.5 transport. Our findings provide clues further characterize functions uptake translocation

Language: Английский

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Fast-forward on P-type ATPases: recent advances on structure and function

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(3), P. 1347 - 1360

Published: June 2, 2023

P-type ATPase are present in nearly all organisms. They maintain electrochemical gradients for many solutes, particular ions, they control membrane lipid asymmetry, and crucial components of intricate signaling networks. All ATPases share a common topology with transmembrane three cytoplasmic domains their transport cycle follows general scheme — the Post-Albers-cycle. Recently, research has been advanced most significantly by technological advancements cryo-EM analysis, which elucidated new structures mechanisms revealed several ways regulation. In this review, we highlight progress field focus on special features that five subfamilies. Hence, outline intersubunit model KdpFABC, heavy metal pumps have evolved to accommodate various substrates, strategies Ca2+ utilize adapt different environmental needs, molecular builds ion binding sites Na,K- H,K-ATPases, remarkable hexameric assembly fungal proton pumps, P4-ATPase flippases regulated, finally deorphanization P5 pumps. Interestingly described found more than one subfamilies, mixed matched together provide optimal function precise

Language: Английский

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Mapping O- and N-Glycosylation in Transmembrane and Interface Regions of Proteins: Insights from a Database Search Study

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 327 - 327

Published: Jan. 2, 2025

Glycosylation is a critical post-translational modification that influences protein folding, stability and function. While extensively studied in extracellular intracellular regions, glycosylation within transmembrane (TM) regions at membrane interfaces remains poorly understood. This study aimed to map O- N-glycosylation sites these using comprehensive database search structural validation where possible. Extensive searches revealed range of proteins. Only the falling TM interface (according Uniprot annotations) were retained. The location was confirmed based on available 3D structures. We identified 32 O-glycosylation 7 domains 29 O-GlcNAc validated as located presented side chains either oriented toward lipid bilayer or buried protein. predicted largely confined domains. results obtained here highlight occurrence proteins interfaces. dataset provides valuable foundation for further exploration functional roles membrane-associated regions.

Language: Английский

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