PROTAC targeted protein degraders: the past is prologue

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(3), P. 181 - 200

Published: Jan. 18, 2022

Language: Английский

---

The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions

Protein Science, Journal Year: 2020, Volume and Issue: 30(1), P. 187 - 200

Published: Oct. 18, 2020

The BioGRID (Biological General Repository for Interaction Datasets, thebiogrid.org) is an open-access database resource that houses manually curated protein and genetic interactions from multiple species including yeast, worm, fly, mouse, human. ~1.93 million in can be used to build complex networks facilitate biomedical discoveries, particularly as related human health disease. All content primary experimental evidence the literature, includes both focused low-throughput studies large high-throughput datasets. also captures post-translational modifications or gene with bioactive small molecules many known drugs. A built-in network visualization tool combines all annotations allows users generate graphs of protein, chemical interactions. In addition general curation across species, undertakes themed projects specific aspects cellular regulation, example ubiquitin-proteasome system, well disease areas, such SARS-CoV-2 virus causes COVID-19 severe acute respiratory syndrome. recent extension BioGRID, named Open CRISPR Screens (ORCS, orcs.thebiogrid.org), single mutant phenotypes published high throughput genome-wide CRISPR/Cas9-based screens. BioGRID-ORCS contains datasets over 1,042 screens carried out date human, mouse fly cell lines. research community freely access data through web interface, standardized file downloads, via model organism databases partner meta-databases.

Language: Английский

---

Molecular mechanisms and physiological functions of mitophagy

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(3)

Published: Jan. 13, 2021

Review13 January 2021Open Access Molecular mechanisms and physiological functions of mitophagy Mashun Onishi orcid.org/0000-0003-1511-4097 Laboratory Mitochondrial Dynamics, Graduate School Frontier Biosciences, Osaka University, Suita, JapanThese authors contributed equally to this work Search for more papers by author Koji Yamano orcid.org/0000-0002-4692-161X The Ubiquitin Project, Tokyo Metropolitan Institute Medical Science, Tokyo, Miyuki Sato Corresponding Author [email protected] orcid.org/0000-0002-1944-4918 Membrane Biology, Cellular Regulation, Gunma Maebashi, Japan Noriyuki Matsuda orcid.org/0000-0001-8199-952X Okamoto orcid.org/0000-0003-4730-4522 Information Onishi1, Yamano2, *,3, *,2 *,1 1Laboratory 2The 3Laboratory *Corresponding author. Tel: +81 27 220 8842; E-mail: 3 5316 3244; 6 6879 7970; EMBO Journal (2021)40:e104705https://doi.org/10.15252/embj.2020104705 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Degradation mitochondria via a selective form autophagy, named mitophagy, is fundamental mechanism conserved from yeast humans that regulates mitochondrial quality quantity control. Mitophagy promoted specific outer membrane receptors, or ubiquitin molecules conjugated proteins on surface leading formation autophagosomes surrounding mitochondria. Mitophagy-mediated elimination plays an important role many processes including early embryonic development, cell differentiation, inflammation, apoptosis. Recent advances analyzing vivo also reveal high rates steady-state turnover diverse types, highlighting intracellular housekeeping mitophagy. Defects are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, aging, further underscoring biological relevance. Here, we review our current molecular understanding its implications, discuss how multiple pathways coordinately modulate fitness populations. ALLO-1 Allophagy-1 ATG Autophagy-related protein BCL2L1/BCL-XL BCL2 like 1 BCL2L13 B-cell lymphoma 2-like 13 BNIP3 adenovirus E1B 19-kDa-interacting BNIP3L Nip3-like X (NIX)/BNIP3-like CCCP Carbonyl cyanide m-chlorophenylhydrazone cGAS Cyclic GMP-AMP synthase CK2 Casein kinase 2 CPS-6 endonuclease G DFCP1/ZFYVE1 DFCP1/zinc finger FYVE-type containing FIP200/RB1CC1 FIP200/RB1-inducible coiled-coil Fis1 Fission, FKBP8/FKBP38 FK506-binding 8 FOXO1 Forkhead box O1 FUNDC1 FUN14 domain-containing GABARAP GABA type A receptor-associated GABARAPL1/2 protein-like 1/2 GFP Green fluorescent HOPS Homotypic fusion vacuole sorting IGF-1 Insulin-like growth factor Keap1 Kelch-like ECH-associated LC3A/B/C Microtubule-associated light chain alpha/beta/gamma LIR LC3-interacting region MARCH5/MITOL Membrane-associated ring-CH-type 5 MBP Maltose-binding Miro Rho mTORC1 Mechanistic target rapamycin complex MUL1 E3 ligase NBR1 autophagy cargo receptor NDP52/CALCOCO2 NDP52/calcium binding domain NLRP3 NLR family pyrin NOD Nucleotide-binding oligomerization NRF2 Nuclear factor, erythroid OPTN Optineurin p62/SQSTM1 p62/Sequestosome PARL Presenilin-associated rhomboid-like PC Phosphatidylcholine PE Phosphatidylethanolamine PGAM5 PGAM member 5, serine/threonine phosphatase PI Phosphatidylinositol PI3K 3-kinase PI3P Phosphatidylinositol-3-phosphate PINK1 PTEN induced PLEKHM1 Pleckstrin homology RUN M1 RABGEF1 RAB guanine nucleotide exchange Rheb Ras homolog, SNARE Soluble N-ethylmaleimide-sensitive attachment Src SRC proto-oncogene, non-receptor tyrosine STING Stimulator interferon genes TAX1BP1 Tax1 TBC1D15 TBC1 15 TBC1D17 17 TBK1 TANK-binding TOMM/TOM Translocase TORC1 Target UBAN Ubiquitin-binding ABIN NEMO ULK1 Unc-51-like activating USP protease VDAC Voltage-dependent anion channel VPS Vacuolar WIPI WD repeat domain, phosphoinositide interacting Introduction Mitochondria double-membrane-bound subcellular compartments function ATP production, phospholipid biosynthesis/transport, calcium signaling, iron homeostasis (Raffaello et al, 2016; Tamura Endo, 2017; Spinelli Haigis, 2018). These organelles act platforms events apoptosis, innate immune response, differentiation (Mehta Kalkavan Green, 2018; Lisowski Since generate reactive oxygen species (ROS) electron transport chain, they constantly challenged oxidative stress ultimately may lead their structural functional failure (Wong 2017). Therefore, cells need sophisticated systems maintaining fitness. control relies pathways: ROS scavenging, DNA repair, refolding/degradation (Scheibye-Knudsen 2015). In addition these processes, fission play key roles (Eisner While promotes content mixing between healthy partially dysfunctional mitochondria, separates damaged components pool. autophagic system targets impaired delivers them lysosomes degradation. This catabolic process, called contributes (Pickles 2018) types. tissues consuming large amount brain, skeletal muscle, heart, liver, kidney, highly developed order maintain proper balance energy demand supply. When shifted normoxia hypoxia, decrease quantity, thereby adapting cellular metabolism anaerobic (Wu Chen, Thus, biogenesis degradation two opposing determine (Ploumi addition, almost completely eliminated during erythrocyte maturation (Ney, Furthermore, accumulating evidence reveals maternal inheritance (mtDNA) depends clearance sperm-derived paternal embryogenesis (Sato Sato, Although generally recognized bulk process non-selectively transports cytoplasmic nucleic acids, proteins, (Nakatogawa, 2020), it acts mediate particular (Gatica one organelle-specific serves structure (Okamoto, 2014) (Fig 1). term "mitophagy" was first coined 2005 (Lemasters, 2005; Priault 2005), within few years, major breakthroughs led discovery selectively (Okamoto 2009; Kanki 2009b) mammalian (Schweers 2007; Narendra 2008; Sandoval 2008). review, will describe underlying yeast, worms, Drosophila, cover pathophysiological functions. Figure 1. Overview (1) Intra- extracellular cues promote isolation excess fragmentation tubular networks. (2) receptors ubiquitin–autophagy adaptors confer selectivity recruited and/or activated (3) Core autophagy-related membrane/phagophore (4) Targeted enclosed sequestrated autophagosomes. (5) Autophagosomes transported fused lytic vacuoles mammals. (6) Lysosomal vacuolar acidic hydrolases flow into degrade contents be recycled. Download figure PowerPoint Receptor-mediated Regulation Atg32 budding Saccharomyces cerevisiae mostly mediated Atg32, single-pass transmembrane (OMM) 2009) 2A). unicellular eukaryote, when grown stationary phase upon nitrogen starvation (Tal Klionsky, 2009). Under conditions, expression at transcriptional level accumulates OMM, forming Atg8 Atg11 localized autophagosomes, scaffold other Atg autophagosome formation. Loss abolishes while overexpression increases activity, suggesting molecule rate-limiting regulating number degraded. specifically dispensable types cytoplasm-to-vacuole targeting pathway, ER-phagy, pexophagy. 2. (A) Schematic representation structures AIM/LIR, Atg8-family protein-interacting motif/LC3-interacting (pink); TM, (light blue); BH1-4, Bcl-2 1-4 (green green); PPlase, peptidyl-prolyl cis-trans isomerase (orange); TPR, tetratricopeptide (purple); CaM, calmodulin-binding (dark red). size indicated amino acids. (B-D) Models activation recruitment surface. (B), BNIP3, BCL2L13, FKBP8 (C), FUNDC1, NIX (D) bind ATG8 then machinery Phosphorylation dephosphorylation serve regulatory activity receptors. For details, see text. Several lines phosphorylation event Atg32-mediated 2B). During respiration shift starvation, phosphorylated manner dependent Atg11-interacting motif Ser114 Ser119 (Aoki 2011; Kondo-Okamoto 2012). Importantly, post-translational modification CK2, evolutionarily variety (Kanki 2013). interacts directly phosphorylates vitro Mutagenesis Ser114, Ser119, residues impairment destabilizes Atg32-Atg11 interactions strongly suppresses 2012; 2013), CK2-dependent could step activate recruiting recent study has demonstrated 2A (PP2A)-like Ppg1 critical negatively (Furukawa lacking Ppg1, even respiratory log (stage prior induction), likely resulting increased accelerate Ppg1-dependent suppression requires partners Far have previously been suggested pheromone-induced cycle arrest (Pracheil Liu, findings raise possibility Ppg1-Far dephosphorylates competing against CK2-mediated under non-inducing conditions. known proteolytically cleaved Yme1, catalytic subunit metalloprotease inner (IMM) belongs ATPases activities (AAA) (Leonhard 1996). Upon processed C-terminal portion Yme1-dependent (Wang 2013) Yme1 leads strong support idea Yme1-mediated proteolysis required efficient However, studies suggest minor no deficiencies (Welter 2013; Gaspard McMaster, 2015), raising processing relevant some strains ER factors connected contact sites ER–mitochondria encounter (ERMES) facilitates transfer (Kornmann ERMES discrete foci where closely positioned, loss severe defects starvation-induced (Bockler Westermann, 2014). component Mmm1 forms co-localize dot-like structures, Ubiquitylation Mdm12/34 Rsp5 linked (Belgareh-Touze regulated Get1/2 Opi3, (Sakakibara 2015; insertion tail-anchored (Schuldiner Schuldiner Wang causes slightly hardly affected (Onishi How trans remains unclear. Surprisingly, methyltransferase ER, induction Opi3 biosynthesis pathway conversion PC. Depletion aberrant elevation glutathione levels reduces thus affects (Deffieu Sakakibara respiring coordinate methylation through unknown mechanisms. mammals mammals, mechanistically than different signals developmental changes. Disruption potential potent trigger (Elmore 2001). CCCP, proton-selective ionophore, antimycin (an inhibitor III) commonly impair Because toxic induces non-physiological damage especially neurons, often induce neuronal (Cai Ashrafi Both reagents depolarization accumulation OMM. integral members (LC3A/B/C, GABARAP, GABARAP-L1/2) regions (LIRs) regulate membranes enclosing Two One group includes (also NIX) (Boyd 1994; Matsushima 1998; Chen 1999; Vande Velde 2000; Regula 2002; Kubli Schweers Hanna 2012), (Liu counterpart (Murakawa 2015) following part, namely FKBP (Bhujabal hypoxic (Zhang response upregulated anchored OMM (TM) exposing N-terminal cytosol (Hanna usually expressed inactive monomer cytosol, but signals, stable homodimer TM integrated (Chen 1997; Ray mutations, which disrupt homodimerization do not affect localization, cause defect, supporting Similar 2A) mutations block interaction LC3, defects. Ser17 Ser24 near BNIP3-LC3 (Zhu 2C). shows (53–56% acid sequence identity) (Matsushima 1999) reticulocyte nucleus, eliminated, so erythrocytes can keep maximum space hemoglobin (Koury Yoshida Fader Colombo, 2006). With similarity restore reticulocytes contains LC3A, LC3B, GABARAP-L1, GABARAP-L2 (Novak 2010) CCCP-treated cells, recruits GABARAP-L1 2010). Ser34 Ser35, tandem serine motif, stabilizes NIX-LC3 (Rogov 2017) 2D). dimerization NIX, region, (Marinkovic 2020). Accumulation (triggered phosphorylation) NIX-mediated LC3 (Melser phosphorylation, Rheb, small GTPase superfamily, translocates mitophagosome Expression HeLa respiration, decreases consumption capacity Whether phenotypes depend Rheb-induced addressed. shown inhibit crucial (Li 2007). As (Bartolome 2017), BNIP3-dependent inhibition might facilitate take part positive feedback loop amplify initiation signal reported PINK1/Parkin-mediated ubiquitylated Parkin, turn adaptor binds both LC3/GABARAP (Gao Parkin translocation 2016a). CCCP-induced depolarization, (Ding 2010b). Pathophysiological relevance Parkinson's disease unknown. hypoxia-induced It typical three domains 2012) Mutations FUNDC1-LC3 OMM-anchored ubiquitylate several acting dynamics (Yonashiro 2006; Sugiura Park decreased hypoxia ubiquitin–proteasome-dependent due MARCH5-mediated ubiquitylation Lys119 Knockdown endogenous MARCH5 mutant impairs enhancing Ser13 Tyr18 located motif. mediates becomes inactivated, causing Tyr18, stabilization promotion enhances Hypoxia (near motif) 2014b). variant defective inhibits normoxic BCL2L1/Bcl-xL, antiapoptotic BH3 molecule, PGAM5-FUNDC1 prevent 2014a). homologs far identified motifs morphology fragmentation, silencing elongation BCL2L13-dependent conventional Atg7, core essential lipidation second reduce absence notion seems contribute regulation BCL2L13-LC3 mutation Ser272 localize 2019). elucidated. immunosuppressant drug FK506 tacrolimus) transcription, folding/trafficking, apoptosis (Bonner Boulianne, Co-overexpression LC3A depolarized CCCP-treated, Parkin-depleted canonical N-terminus C-terminus preferentially over vivo, Moreover, escape degradation-prone localizes (Saita Bhujabal Given complexity versatile needed clarify whether involved Ubiquitin-mediated (PD) neurodegenerative characterized death dopaminergic neurons (Lotharius Brundin, 2002). PD occurs sporadically 1–2% people above 65 years age arise earlier genetic mutations. Common observed patients motor symptoms (tremor, bradykinesia, rigidity, postural instability) result substantia nigra. Non-motor autono

Language: Английский

---

Autophagy in Human Diseases

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 383(16), P. 1564 - 1576

Published: Oct. 14, 2020

Autophagy is a complex process of intracellular degradation senescent or malfunctioning organelles. Dysregulated autophagy associated with certain cancers, neurodegenerative diseases, immune dysfunction, and aging. Therapies aimed at regulating are being developed.

Language: Английский

---

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(9), P. 609 - 633

Published: July 24, 2020

Language: Английский

---

The mechanisms and roles of selective autophagy in mammals

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 167 - 185

Published: Oct. 27, 2022

Language: Английский

---

PROTACs: great opportunities for academia and industry

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Dec. 24, 2019

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic limited number drug targets, which presently only 20-25% all protein targets that currently being studied. Moreover, focus current explorations their enzymatic functions, ignores functions from scaffold moiety. As promising appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both academia industry for finding available approaches to solve above problems. PROTACs regulate function by degrading target proteins instead inhibiting them, providing more sensitivity drug-resistant greater chance affect nonenzymatic functions. been proven show better selectivity compared classic inhibitors. can be described as chemical knockdown approach with rapidity reversibility, presents new different biology other gene editing tools avoiding misinterpretations arise potential genetic compensation and/or spontaneous mutations. PRTOACs widely explored throughout world outperformed not cancer diseases, but also immune disorders, viral infections neurodegenerative diseases. present very powerful crossing hurdles discovery tool development biology, efforts needed gain get deeper insight into efficacy safety clinic. More binders E3 ligases applicable developing waiting exploration.

Language: Английский

---

Targeted protein degradation: mechanisms, strategies and application

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Language: Английский

---

PROTACs: past, present and future

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(12), P. 5214 - 5236

Published: Jan. 1, 2022

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein interest (POI) and another can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI ligase results in ubiquitination subsequent degradation by ubiquitin-proteasome system (UPS). event-driven mechanism action (MOA) PROTACs offers several advantages compared traditional occupancy-driven small molecule inhibitors, such as catalytic nature, reduced dosing frequency, more potent longer-lasting effect, added layer selectivity reduce potential toxicity, efficacy face drug-resistance mechanisms, targeting nonenzymatic functions, expanded target space. Here, we highlight important milestones briefly discuss lessons learned about targeted (TPD) recent years conjecture on efforts still needed expand toolbox for PROTAC discovery ultimately provide promising therapeutics.

Language: Английский

---

Targeting p53 pathways: mechanisms, structures and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

---