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

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(31)

Published: July 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

Language: Английский

Exploration of Degrons and Their Ability to Mediate Targeted Protein Degradation DOI
Timothy J. Harris, Darci J. Trader

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Degrons are regions of a protein that required to initiate their degradation by cellular machinery.

Language: Английский

Citations

1
Structural and Functional Insights into GID/CTLH E3 Ligase Complexes DOI Open Access
Matthew E. R. Maitland, Gilles Lajoie, Gary S. Shaw

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 5863 - 5863

Published: May 24, 2022

Multi-subunit E3 ligases facilitate ubiquitin transfer by coordinating various substrate receptor subunits with a single catalytic center. Small molecules inducing targeted protein degradation have exploited such complexes, proving successful as therapeutics against previously undruggable targets. The C-terminal to LisH (CTLH) complex, also called the glucose-induced deficient (GID) is multi-subunit ligase complex highly conserved from Saccharomyces cerevisiae humans, roles in fundamental pathways controlling homeostasis and development several species. However, we are only beginning understand its mechanistic basis. Here, review literature of CTLH all organisms place previous findings on individual into context recent breakthroughs structure function.

Language: Английский

Citations

36
Elucidation of E3 ubiquitin ligase specificity through proteome-wide internal degron mapping DOI Creative Commons
Zhiqian Zhang, Brandon Sie, Aiquan Chang

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(18), P. 3377 - 3392.e6

Published: Sept. 1, 2023

The ubiquitin-proteasome system plays a critical role in biology by regulating protein degradation. Despite their importance, precise recognition specificity is known for few of the 600 E3s. Here, we establish two-pronged strategy identifying and mapping residues internal degrons on proteome-scale HEK-293T cells. We employ global stability profiling combined with machine learning to identify 15,800 peptides likely contain sequence-dependent degrons. combine this scanning mutagenesis define over 5,000 predicted Focusing Cullin-RING ligase degrons, generated mutational fingerprints 219 developed DegronID, computational algorithm enabling clustering degron similar motifs. CRISPR analysis enabled discovery E3-degron pairs, which uncovered 16 pairs that revealed extensive variability structural determinants. provide visualization these data public DegronID browser as resource future exploration.

Language: Английский

Citations

21
Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism DOI Open Access

Seo-Young Koo,

Eun‐Ji Park,

Hyun-Ji Noh

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 8441 - 8441

Published: May 8, 2023

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events which recognized, repair recruited site damage, lesion repaired, responses associated with processed. In cancer, commonly dysregulated, enzymes prone changes ubiquitination. Additionally, metabolism, especially glycolysis, upregulated cells, this metabolic pathway modulated by The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as bridge between since they regulate processes. Hence, ligases high substrate specificity considered potential therapeutic targets for treating cancer. A number small molecule inhibitors designed target different components UPS have been developed, several tested clinical trials human use. review, we discuss role ubiquitination on overall confirm link them through NEDD4, APC/CCDH1, FBXW7, Pellino1. addition, present an overview clinically implications their practical

Language: Английский

Citations

20
The lowdown on breakdown: Open questions in plant proteolysis DOI Creative Commons
Nancy A. Eckardt, Tamar Avin‐Wittenberg, Diane C. Bassham

et al.

The Plant Cell, Journal Year: 2024, Volume and Issue: 36(9), P. 2931 - 2975

Published: July 9, 2024

Abstract Proteolysis, including post-translational proteolytic processing as well protein degradation and amino acid recycling, is an essential component of the growth development living organisms. In this article, experts in plant proteolysis pose discuss compelling open questions their areas research. Topics covered include role cell cycle, DNA damage response, mitochondrial function, generation N-terminal signals (degrons) that mark many proteins for (N-terminal acetylation, Arg/N-degron pathway, chloroplast N-degron pathway), developmental metabolic signaling (photomorphogenesis, abscisic strigolactone signaling, sugar metabolism, postharvest regulation), responses to environmental (endoplasmic-reticulum-associated degradation, chloroplast-associated drought tolerance, growth-defense trade-off), functional diversification peptidases. We hope these thought-provoking discussions help stimulate further

Language: Английский

Citations

8
An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses DOI Creative Commons
Linjuan Wu, Liming Zhang,

Shengyong Feng

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(16)

Published: April 9, 2024

Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions infections annually. The single-stranded RNA genome is translated into a polyprotein, which cleaved equally individual functional proteins. While structural proteins are packaged progeny virions released, most the nonstructural remain intracellular could become cytotoxic if accumulated over time. However, mechanism by maintained at levels optimal for cellular fitness viral replication remains unknown. Here, we identified that ubiquitin E3 ligase HRD1 essential in both mammalian hosts mosquitoes. directly interacts with flavivirus NS4A ubiquitylates conserved lysine residue ER-associated degradation. This avoids excessive accumulation NS4A, otherwise interrupts expression processed ER. Furthermore, small-molecule inhibitor named LS-102 effectively DENV2 infection mice Aedes aegypti mosquitoes, significantly disturbs DENV transmission from infected to mosquitoes owing reduced viremia. Taken together, this study demonstrates have evolved sophisticated exploit ubiquitination system balance homeostasis their own advantage provides potential therapeutic target interrupt transmission.

Language: Английский

Citations

7
A chemical probe to modulate human GID4 Pro/N-degron interactions DOI
Dominic D. G. Owens, Matthew E. R. Maitland,

Aliakbar Khalili Yazdi

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(9), P. 1164 - 1175

Published: May 21, 2024

Language: Английский

Citations

7
The role of ubiquitination in health and disease DOI Creative Commons

Yan Liao,

Wangzheqi Zhang,

Yang Liu

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(10)

Published: Sept. 25, 2024

Ubiquitination is an enzymatic process characterized by the covalent attachment of ubiquitin to target proteins, thereby modulating their degradation, transportation, and signal transduction. By precisely regulating protein quality quantity, ubiquitination essential for maintaining homeostasis, DNA repair, cell cycle regulation, immune responses. Nevertheless, diversity enzymes extensive involvement in numerous biological processes contribute complexity variety diseases resulting from dysregulation. The relies on a sophisticated system, domains, receptors, which collectively impart versatility pathway. widespread presence highlights its potential induce pathological conditions. Ubiquitinated proteins are predominantly degraded through proteasomal also plays key role localization transport, as well inflammatory pathways. This review systematically delineates roles genomic stability, cellular proliferation, Furthermore, mechanisms implicated various pathologies, alongside current modulators discussed. Enhancing our comprehension aims provide novel insights into involving propose innovative therapeutic strategies clinical

Language: Английский

Citations

7
UPS-dependent strategies of protein quality control degradation DOI Creative Commons

Leonie Müller,

Thorsten Hoppe

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(10), P. 859 - 874

Published: June 29, 2024

Language: Английский

Citations

6
A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells DOI
Fang Liu, Xuan Wang,

Jianli Duan

et al.

Advanced Science, Journal Year: 2022, Volume and Issue: 9(22)

Published: June 2, 2022

Abstract AURKA is a potential kinase target in various malignancies. The kinase‐independent oncogenic functions partially disclose the inadequate efficacy of inhibitor Phase III clinical trial. Simultaneously targeting catalytic and noncatalytic may be feasible approach. Here, set proteolysis chimeras (PROTACs) are developed. CRBN‐based dAurA383 preferentially degrades highly abundant mitotic AURKA, while cIAP‐based dAurA450 lowly interphase acute myeloid leukemia (AML) cells. proteomic transcriptomic analyses indicate that triggers “mitotic cell cycle” “stem cell” processes, inhibits “MYC/E2F targets” processes. combined as PROTAC cocktail. cocktail effectively relieves hook effect, synergistically AML stem Furthermore, induces regression xenograft mouse model primary patient blasts. These findings establish promising spatial‐temporal drug administration strategy to sequentially eliminate multifaceted oncoproteins, relieve prevent cancer cell‐mediated resistance.

Language: Английский

Citations

26