Apoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells toward apoptosis, differentiation, and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular, and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers our ability to target this member of the MAP3K protein family towards developing therapeutic interventions for these disorders. Nevertheless, as a multidomain Ser/Thr protein kinase, ASK1 is regulated by a complex mechanism involving dimerization and interactions with several other proteins, including thioredoxin 1 (TRX1). Thus, the present study aims at structurally characterizing ASK1 and its complex with TRX1 using several biophysical techniques. As shown by cryo-EM analysis, in a state close to its active form, ASK1 is a compact and asymmetric dimer, which enables extensive interdomain and interchain interactions. These interactions stabilize the active conformation of the ASK1 kinase domain. In turn, TRX1 functions as a negative allosteric effector of ASK1, modifying the structure of the TRX1-binding domain and changing its interaction with the tetratricopeptide repeats domain. Consequently, TRX1 reduces access to the activation segment of the kinase domain. Overall, our findings not only clarify the role of ASK1 dimerization and inter-domain contacts but also provide key mechanistic insights into its regulation, thereby highlighting the potential of ASK1 protein-protein interactions as targets for anti-inflammatory therapy.

• Klíčová slova
• ASK1, MAP3K, MAPK signaling, biochemistry, chemical biology, human, molecular biophysics, protein kinase, structural biology, thioredoxin,
• MeSH
• apoptóza MeSH
• biofyzika MeSH
• elektronová kryomikroskopie MeSH
• MAP kinasa-kinasa-kinasa 5 * MeSH
• thioredoxiny * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• MAP kinasa-kinasa-kinasa 5 * MeSH
• thioredoxiny * MeSH

Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer's, Parkinson's and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.

• Klíčová slova
• 14-3-3, ASK1, MAP kinase, kinase, phosphorylation, protein–protein interaction,
• MeSH
• apoptóza fyziologie   MeSH
• fosforylace MeSH
• JNK mitogenem aktivované proteinkinasy metabolismus   MeSH
• lidé MeSH
• MAP kinasa-kinasa-kinasa 5 genetika   metabolismus   fyziologie   ultrastruktura   MeSH
• MAP kinasový signální systém MeSH
• MAP kinasy kinas (kinas) genetika   metabolismus   MeSH
• mapy interakcí proteinů genetika   fyziologie   MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• proteiny 14-3-3 metabolismus   MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• stres endoplazmatického retikula MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• JNK mitogenem aktivované proteinkinasy MeSH
• MAP kinasa-kinasa-kinasa 5 MeSH
• MAP kinasy kinas (kinas) MeSH
• MAP3K5 protein, human MeSH Prohlížeč
• mitogenem aktivované proteinkinasy p38 MeSH
• proteiny 14-3-3 MeSH
• proteiny regulující apoptózu MeSH

Inflammation is among the core causatives of male infertility. Despite male infertility being a serious global issue, "bits and pieces" of its complex etiopathology still remain missing. During inflammation, levels of proinflammatory mediators in the male reproductive tract are greater than usual. According to epidemiological research, in numerous cases of male infertility, patients suffer from acute or chronic inflammation of the genitourinary tract which typically occurs without symptoms. Inflammatory responses in the male genital system are inextricably linked to oxidative stress (OS). OS is detrimental to male fertility parameters as it causes oxidative damage to reproductive cells and intracellular components. Multifarious male infertility causative factors pave the way for impairing male reproductive functions via the common mechanisms of OS and inflammation, both of which are interlinked pathophysiological processes, and the occurrence of any one of them induces the other. Both processes may be simultaneously found in the pathogenesis of male infertility. Thus, the present article aims to explain the role of inflammation and OS in male infertility in detail, as well as to show the mechanistic pathways that link causative factors of male reproductive tract inflammation, OS induction, and oxidant-sensitive cellular cascades leading to male infertility.

• Klíčová slova
• cytokines, inflammation, male infertility, oxidative stress, reactive oxygen species,
• MeSH
• cytokiny metabolismus   MeSH
• infertilita patofyziologie   MeSH
• lidé MeSH
• mužské pohlavní orgány metabolismus   MeSH
• oxidační stres genetika   fyziologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zánět metabolismus   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH
• reaktivní formy kyslíku MeSH

Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Unsurprisingly, tight and precise kinase regulation is a prerequisite for normal cell functioning, whereas kinase dysregulation often leads to disease. Moreover, the functions of many kinases are regulated through protein-protein interactions, which in turn are mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. Therefore, the aim of this review article is to provide an overview of the state of the art on 14-3-3-mediated kinase regulation, focusing on the most recent mechanistic insights into these important protein-protein interactions and discussing in detail both their structural aspects and functional consequences.

• Klíčová slova
• 14-3-3, ASK1, CaMKK2, LRRK2, PI4KB, PKC, RAF kinase, kinase, phosphorylation,
• MeSH
• alosterická regulace genetika   MeSH
• apoptóza genetika   MeSH
• fosforylace genetika   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 genetika   MeSH
• proteinkinasy genetika   MeSH
• proteiny 14-3-3 genetika   MeSH
• signální transdukce genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• mitogenem aktivované proteinkinasy p38 MeSH
• proteinkinasy MeSH
• proteiny 14-3-3 MeSH