Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates DOI Creative Commons

Bong Heon Kim,

Min Kyung Kim,

Sun Joo Oh

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(31)

Опубликована: Июль 25, 2022

N-degron pathways are proteolytic systems that target proteins bearing N-terminal (Nt) degradation signals (degrons) called N-degrons. Nt-Arg of a protein is among Nt-residues can be recognized as destabilizing ones by the Arg/N-degron pathway. A cleavage generate Arg at N terminus resulting C-terminal (Ct) fragment either directly or after Nt-arginylation Ct-fragment Ate1 arginyl-tRNA-protein transferase (R-transferase), which uses Arg-tRNA cosubstrate. Nt-arginylate Nt-Asp, Nt-Glu, and oxidized Nt-Cys* (Cys-sulfinate Cys-sulfonate) short peptides. genes fungi, animals, plants have been cloned decades ago, but three-dimensional structure remained unknown. detailed mechanism arginylation unknown well. We describe here crystal R-transferase from budding yeast Kluyveromyces lactis . The 58-kDa comprises two domains recognize, together, an acidic Nt-residue acceptor substrate, residue , 3′-proximal segment tRNA moiety. enzyme’s active site located, least in part, between domains. In vitro vivo assays with site-directed mutants were suggested structural results yielded inferences about specific binding sites Ate1. also analyzed inhibition activity hemin (Fe 3+ -heme), found induced previously undescribed disulfide-mediated oligomerization Together, these advance understanding

Язык: Английский

Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules DOI
Christopher M. Hickey, Katherine M. Digianantonio, Kurt Zimmermann

и другие.

Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(2), С. 311 - 322

Опубликована: Янв. 4, 2024

Язык: Английский

Процитировано

25
The next wave of interactomics: Mapping the SLiM-based interactions of the intrinsically disordered proteome DOI Creative Commons
Norman E. Davey, Leandro Simonetti, Ylva Ivarsson

и другие.

Current Opinion in Structural Biology, Год журнала: 2023, Номер 80, С. 102593 - 102593

Опубликована: Апрель 24, 2023

Short linear motifs (SLiMs) are a unique and ubiquitous class of protein interaction modules that perform key regulatory functions drive dynamic complex formation. For decades, interactions mediated by SLiMs have accumulated through detailed low-throughput experiments. Recent methodological advances opened this previously underexplored area the human interactome to high-throughput protein–protein discovery. In article, we discuss SLiM-based represent significant blind spot in current interactomics data, introduce methods illuminating elusive SLiM-mediated cell on large scale, implications for field.

Язык: Английский

Процитировано

31
Protein degradation: expanding the toolbox to restrain cancer drug resistance DOI Creative Commons
Hui Ming, Bowen Li, Jingwen Jiang

и другие.

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Янв. 24, 2023

Abstract Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib proteolysis-targeting chimeric have been developed. Compared intervention at the transcriptional level, targeting process seems be more rapid direct strategy. Proteasomal proteolysis lysosomal are most critical quality control systems responsible for proteins or organelles. Although proteasomal inhibitors (e.g., chloroquine) achieved certain improvements some application scenarios, their routine practice is still long way off, which due lack precise capabilities inevitable side effects. In-depth studies regulatory mechanism regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), chaperones, expected provide clues developing reducing Here, we discuss underlying mechanisms regulating efflux, metabolism, DNA repair, target alteration, downstream bypass signaling, sustaining stemness, tumor microenvironment remodeling delineate functional roles resistance. We also highlight specific DUBs, discussing possible modulating cancer A systematic summary molecular basis by regulates will help facilitate development appropriate strategies.

Язык: Английский

Процитировано

30
Structure of the human UBR5 E3 ubiquitin ligase DOI Creative Commons
Feng Wang, Qing He, Wenhu Zhan

и другие.

Structure, Год журнала: 2023, Номер 31(5), С. 541 - 552.e4

Опубликована: Апрель 10, 2023

Язык: Английский

Процитировано

28
E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity DOI Creative Commons
Daniel C. Scott, Moeko T. King, Kheewoong Baek

и другие.

Molecular Cell, Год журнала: 2023, Номер 83(5), С. 770 - 786.e9

Опубликована: Фев. 16, 2023

Язык: Английский

Процитировано

26
The ubiquitin–proteasome system links NADPH metabolism to ferroptosis DOI
Jihye Yang, Yoontae Lee, Cheol‐Sang Hwang

и другие.

Trends in Cell Biology, Год журнала: 2023, Номер 33(12), С. 1088 - 1103

Опубликована: Авг. 7, 2023

Язык: Английский

Процитировано

24
N-degron pathways DOI Creative Commons
Alexander Varshavsky

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(39)

Опубликована: Сен. 12, 2024

An N-degron is a degradation signal whose main determinant “destabilizing” N-terminal residue of protein. Specific N-degrons, discovered in 1986, were the first identified signals short-lived intracellular proteins. These N-degrons are recognized by ubiquitin-dependent proteolytic system called Arg/N-degron pathway. Although bacteria lack ubiquitin system, they also have pathways. Studies after 1986 shown that all 20 amino acids genetic code can act, specific sequence contexts, as destabilizing residues. Eukaryotic proteins targeted for conditional or constitutive at least five systems differ both functionally and mechanistically: pathway, Ac/N-degron Pro/N-degron fMet/N-degron newly named, this perspective, GASTC/N-degron pathway (GASTC = Gly, Ala, Ser, Thr, Cys). I discuss these expanded terminology now encompasses entire gamut known

Язык: Английский

Процитировано

13
Integrated Multiomics Reveals Silencing of has_circ_0006646 Promotes TRIM21‐Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis DOI Creative Commons
Xin Hu, Guanrong Chen,

Yingchen Huang

и другие.

Advanced Science, Год журнала: 2024, Номер 11(16)

Опубликована: Фев. 15, 2024

Abstract Recent studies suggest that circular RNA (circRNA)‐mediated post‐translational modification of RNA‐binding proteins (RBP) plays a pivotal role in metastasis hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile regulatory networks circRNA RBP using multi‐omics approach. Has_circ_0006646 (circ0006646) is an unreported HCC associated with poor prognosis. Silencing circ0006646 significantly hinders vivo. Mechanistically, prevents interaction between nucleolin (NCL) E3 ligase tripartite motif‐containing 21 reduce proteasome‐mediated degradation NCL via K48‐linked polyubiquitylation. Furthermore, change expression proven affect phosphorylation levels multiple inhibit p53 translation. Moreover, patient‐derived tumor xenograft lentivirus injection, which conducted simulate treatment confirmed value. Overall, this describes integrated landscape circRNA‐mediated ubiquitination provides novel target.

Язык: Английский

Процитировано

10
Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism DOI Creative Commons

Karthik V Gottemukkala,

Jakub Chrustowicz, Dawafuti Sherpa

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(10), С. 1948 - 1963.e11

Опубликована: Май 1, 2024

The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs metabolic enzyme substrates. orthologous higher eukaryotic C-terminal to LisH (CTLH) complex has been proposed also recognize substrates through an alternative subunit, WDR26, which promotes the formation supramolecular CTLH assemblies. Here, we discover human WDR26 binds nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its E3-dependent ubiquitylation independently canonical GID/CTLH E3-family substrate receptors. subunit YPEL5 inhibits NMNAT1 cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated activation cytotoxicity prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures NMNAT1- YPEL5-bound reveal internal basic motif essential for targeting mimicry YPEL5's N terminus antagonizing binding. Thus, our data provide mechanistic understanding how YPEL5-WDR26-CTLH acts as modulator NMNAT1-dependent metabolism.

Язык: Английский

Процитировано

10
The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments DOI Creative Commons
Marcin J. Suskiewicz

BioEssays, Год журнала: 2024, Номер 46(3)

Опубликована: Янв. 21, 2024

Abstract Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels their chemical catalytic underpinnings. Here, focussing on that involve addition new elements to amino‐acid sidechains, I describe historical milestones fundamental concepts support current understanding PTMs. The survey covers selected key research programmes, including study phosphorylation as regulatory switch, ubiquitylation degradation signal histone functional code. contribution techniques for studying PTMs is also discussed. central part essay explores shared principles strategies observed across diverse systems, together with mechanisms substrate selection, reversibility erasers recognition reader domains. Similarities basic mechanism are highlighted implications final dedicated evolutionary trajectories beginning possible emergence context rivalry prokaryotic world. Together, provides unified perspective world major modifications.

Язык: Английский

Процитировано

9