RedOx regulation of LRRK2 kinase activity by active site cysteines DOI Creative Commons
Chiara R. Trilling, Jui-Hung Weng, Pallavi Kaila Sharma

и другие.

npj Parkinson s Disease, Год журнала: 2024, Номер 10(1)

Опубликована: Апрель 3, 2024

Abstract Mutations of the human leucine-rich repeat kinase 2 (LRRK2) have been associated with both, idiopathic and familial Parkinson’s disease (PD). Most these pathogenic mutations are located in domain (KD) or GTPase LRRK2. In this study we describe a mechanism which protein activity can be modulated by reversible oxidation reduction, involving unique pair adjacent cysteines, “CC” motif. Among all kinases, only LRRK2 contains motif (C2024 C2025) Activation Segment (AS) domain. an approach combining site-directed mutagenesis, biochemical analyses, cell-based assays, Gaussian accelerated Molecular Dynamics (GaMD) simulations could attribute role for each those cysteines. We employed reducing oxidizing agents potential clinical relevance to investigate effects on microtubule docking. find that cysteine gives distinct contribution: first cysteine, C2024, is essential activity, while C2025, contributes significantly redox sensitivity. Implementing thiolates (R-S - ) GaMD allowed us analyse how cysteines interacts its surrounding residues depending state. From our studies conclude downregulate hyperactive PD may provide promising tools therapeutic strategies.

Язык: Английский

Reactive oxygen species signalling in plant stress responses DOI
Ron Mittler, Sara I. Zandalinas, Yosef Fichman

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 23(10), С. 663 - 679

Опубликована: Июнь 27, 2022

Язык: Английский

Процитировано

1180
Stress-induced reactive oxygen species compartmentalization, perception and signalling DOI

Bardo Castro,

Matteo Citterico, Sachie Kimura

и другие.

Nature Plants, Год журнала: 2021, Номер 7(4), С. 403 - 412

Опубликована: Апрель 12, 2021

Язык: Английский

Процитировано

331
Cysteine Oxidation in Proteins: Structure, Biophysics, and Simulation DOI Creative Commons
Diego Garrido Ruiz, Angélica Sandoval‐Pérez, Amith Vikram Rangarajan

и другие.

Biochemistry, Год журнала: 2022, Номер 61(20), С. 2165 - 2176

Опубликована: Сен. 26, 2022

Cysteine side chains can exist in distinct oxidation states depending on the pH and redox potential of environment, cysteine plays important yet complex regulatory roles. Compared with effects post-translational modifications such as phosphorylation, to sulfenic, sulfinic, sulfonic acid protein structure function remain relatively poorly characterized. We present an analysis role reactivity a factor proteins, emphasizing interplay between electrostatics key determinants resulting state. A review current computational approaches suggests underdeveloped areas research for studying through molecular simulations.

Язык: Английский

Процитировано

81
Emerging roles of Aurora-A kinase in cancer therapy resistance DOI Creative Commons
Dayong Zheng, Jun Li, Han Yan

и другие.

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 13(7), С. 2826 - 2843

Опубликована: Март 15, 2023

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A occurs different types cancer, lung colorectal breast cancer. Alteration impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape cell death resistance which are involved progression resistance. This review highlights the most recent advances oncogenic roles related hallmarks kinase-driving therapy resistance, chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted (osimertinib, imatinib, sorafenib, etc.), endocrine (tamoxifen, fulvestrant) radioresistance. Specifically, mechanisms promote acquired through modulating DNA damage repair, feedback activation bypass pathways, to apoptosis, necroptosis autophagy, metastasis, stemness. Noticeably, our also summarizes promising synthetic lethality strategy for inhibitors RB1, ARID1A MYC gene mutation tumors, potential synergistic mTOR, PAK1, MDM2, MEK PD-L1 antibodies combined with targeting kinase. In addition, we discuss design development novel class precision medicine treatment.

Язык: Английский

Процитировано

46
A critical evaluation of protein kinase regulation by activation loop autophosphorylation DOI Creative Commons
Ronja Reinhardt, Thomas A. Leonard

eLife, Год журнала: 2023, Номер 12

Опубликована: Июль 20, 2023

Phosphorylation of proteins is a ubiquitous mechanism regulating their function, localization, or activity. Protein kinases, enzymes that use ATP to phosphorylate protein substrates are, therefore, powerful signal transducers in eukaryotic cells. The phosphoryl-transfer universally conserved among which necessitates the tight regulation kinase activity for orchestration cellular processes with high spatial and temporal fidelity. In response stimulus, many kinases enhance own by autophosphorylating amino acid activation loop, but precisely how this reaction performed controversial. Classically, autophosphorylate loop are thought perform trans , mediated transient dimerization domains. However, motivated recently discovered cis -autophosphorylation autoinhibited we here review various mechanisms autoregulation have been proposed. We provide framework critically evaluating biochemical, kinetic, structural evidence autophosphorylation, share some thoughts on implications these within physiological signaling networks.

Язык: Английский

Процитировано

34
Phosphorylated transcription factor PuHB40 mediates ROS-dependent anthocyanin biosynthesis in pear exposed to high light DOI
Lu Zhang, Lu Wang,

Yongchen Fang

и другие.

The Plant Cell, Год журнала: 2024, Номер 36(9), С. 3562 - 3583

Опубликована: Июнь 6, 2024

Abstract Plants are increasingly vulnerable to environmental stresses because of global warming and climate change. Stress-induced reactive oxygen species (ROS) accumulation results in plant cell damage, even death. Anthocyanins important antioxidants that scavenge ROS maintain homeostasis. However, the mechanism underlying ROS-induced anthocyanin is unclear. In this study, we determined HD-Zip I family member transcription factor PuHB40 mediates ROS-dependent biosynthesis under high-light stress pear (Pyrus ussuriensis). Specifically, induces PuMYB123-like–PubHLH3 complex for biosynthesis. The PuHB40-mediated transcriptional activation depends on its phosphorylation level, which regulated by protein phosphatase PP2A. Elevated content maintains high levels while also enhancing PuHB40-induced PuMYB123-like decreasing PuPP2AA2 expression, ultimately leading increased Our study reveals a pathway regulating pears, further clarifying abiotic stress-induced biosynthesis, may have implications improving tolerance.

Язык: Английский

Процитировано

10
Oxidative stress-mediated protein sulfenylation in human diseases: Past, present, and future DOI Creative Commons

Baoquan Mu,

Yan Zeng, Li Luo

и другие.

Redox Biology, Год журнала: 2024, Номер 76, С. 103332 - 103332

Опубликована: Авг. 30, 2024

Reactive Oxygen Species (ROS) refer to a variety of derivatives molecular oxygen that play crucial roles in regulating wide range physiological and pathological processes. Excessive ROS levels can cause oxidative stress, leading cellular damage even cell demise. However, moderately elevated mediate the post-translational modifications (oxPTMs) redox-sensitive proteins, thereby affecting protein functions various signaling pathways. Among oxPTMs, ROS-induced reversible sulfenylation represents initial form cysteine oxidation for sensing redox signaling. In this review, we will summarize discovery, chemical formation, detection approaches sulfenylation. addition, highlight recent findings diseases, including thrombotic disorders, diabetes, cardiovascular neurodegenerative cancer.

Язык: Английский

Процитировано

10
A mitotic NADPH upsurge promotes chromosome segregation and tumour progression in aneuploid cancer cells DOI
Aoxing Cheng, Xu Tian,

Weiyi You

и другие.

Nature Metabolism, Год журнала: 2023, Номер 5(7), С. 1141 - 1158

Опубликована: Июнь 22, 2023

Язык: Английский

Процитировано

21
A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms DOI Creative Commons
Min Cao,

Alison M. Day,

Martin Galler

и другие.

Molecular Cell, Год журнала: 2023, Номер 83(17), С. 3140 - 3154.e7

Опубликована: Авг. 11, 2023

Peroxiredoxins (Prdxs) utilize reversibly oxidized cysteine residues to reduce peroxides and promote H2O2 signal transduction, including H2O2-induced activation of P38 MAPK. Prdxs form disulfide complexes with many proteins, multiple kinases involved in MAPK signaling. Here, we show that a genetically encoded fusion between Prdx is sufficient hyperactivate the kinase yeast human cells by mechanism does not require H2O2-sensing Prdx. We demonstrate P38-Prdx protein compensates for loss scaffold Mcs4 MAP3K activity, driving into mitosis. Based on our findings, propose formation Prdx-MAPK provides an alternative signaling platform MAPKK-MAPK The demonstration complex modify activity has broad implications peroxide-based transduction eukaryotes.

Язык: Английский

Процитировано

18
Navigating the redox landscape: reactive oxygen species in regulation of cell cycle DOI Creative Commons

Viktoria Mackova,

Martina Raudenská, Hana Polanská

и другие.

Redox Report, Год журнала: 2024, Номер 29(1)

Опубликована: Июль 7, 2024

Objectives: To advance our knowledge of disease mechanisms and therapeutic options, understanding cell cycle regulation is critical. Recent research has highlighted the importance reactive oxygen species (ROS) in regulation. Although excessive ROS levels can lead to age-related pathologies, also play an essential role normal cellular functions. Many regulatory proteins are affected by their redox status, but precise conditions under which promote or inhibit proliferation not fully understood.

Язык: Английский

Процитировано

9