Abstract:
:The eukaryotic 26S proteasome controls cellular processes by degrading specific regulatory proteins. Most proteins are targeted for degradation by a signal or degron that consists of two parts: a proteasome-binding tag, typically covalently attached polyubiquitin chains, and an unstructured region that serves as the initiation region for proteasomal proteolysis. Here we have characterized how the arrangement of the two degron parts in a protein affects degradation. We found that a substrate is degraded efficiently only when its initiation region is of a certain minimal length and is appropriately separated in space from the proteasome-binding tag. Regions that are located too close or too far from the proteasome-binding tag cannot access the proteasome and induce degradation. These spacing requirements are different for a polyubiquitin chain and a ubiquitin-like domain. Thus, the arrangement and location of the proteasome initiation region affect a protein's fate and are important in selecting proteins for proteasome-mediated degradation.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Inobe T,Fishbain S,Prakash S,Matouschek Adoi
10.1038/nchembio.521subject
Has Abstractpub_date
2011-03-01 00:00:00pages
161-7issue
3eissn
1552-4450issn
1552-4469pii
nchembio.521journal_volume
7pub_type
杂志文章abstract::Biosynthesis enables renewable production of manifold compounds, yet often biosynthetic performance must be improved for it to be economically feasible. Nongenetic, cell-to-cell variations in protein and metabolite concentrations are naturally inherent, suggesting the existence of both high- and low-performance varian...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.2046
更新日期:2016-05-01 00:00:00
abstract::Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a tar...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.492
更新日期:2011-01-01 00:00:00
abstract::The P1B-ATPases, which couple cation transport across membranes to ATP hydrolysis, are central to metal homeostasis in all organisms. An important feature of P1B-ATPases is the presence of soluble metal binding domains (MBDs) that regulate transport activity. Only one type of MBD has been characterized extensively, bu...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1863
更新日期:2015-09-01 00:00:00
abstract::Serine hydrolases play diverse roles in regulating host-pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here we describe a chemical proteomic screen that identified ten previously uncharacterized S. aureus serine hydrolases that mostly lack h...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/s41589-018-0060-1
更新日期:2018-06-01 00:00:00
abstract::N(1)-Methyladenosine (m(1)A) is a prevalent post-transcriptional RNA modification, yet little is known about its abundance, topology and dynamics in mRNA. Here, we show that m(1)A is prevalent in Homo sapiens mRNA, which shows an m(1)A/A ratio of ∼0.02%. We develop the m(1)A-ID-seq technique, based on m(1)A immunoprec...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.2040
更新日期:2016-05-01 00:00:00
abstract::Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these 'bifunction...
journal_title:Nature chemical biology
pub_type: 杂志文章,评审
doi:10.1038/s41589-020-0469-1
更新日期:2020-04-01 00:00:00
abstract::Molecular dynamics are essential for protein function. In some cases these dynamics involve the interconversion between ground state, highly populated conformers and less populated higher energy structures ('excited states') that play critical roles in biochemical processes. Here we describe recent advances in NMR spe...
journal_title:Nature chemical biology
pub_type: 杂志文章,评审
doi:10.1038/nchembio.238
更新日期:2009-11-01 00:00:00
abstract::A required course in communication at the graduate school level may help cure the disorder of poor scientific writing. ...
journal_title:Nature chemical biology
pub_type: 社论
doi:10.1038/nchembio0906-443
更新日期:2006-09-01 00:00:00
abstract::In eukaryotes, cytosolic monothiol glutaredoxins are proteins implicated in intracellular iron trafficking and sensing via their bound [2Fe-2S] clusters. We define a new role of human cytosolic monothiol glutaredoxin-3 (GRX3) in transferring its [2Fe-2S] clusters to human anamorsin, a physical and functional protein p...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1892
更新日期:2015-10-01 00:00:00
abstract::Single-molecule observations reveal that lipid- and protein-based interactions jointly contribute to the interactions among glycosylphosphatidylinositol-anchored proteins in membranes. Understanding these interactions will help to refine long-evolving (and still debated) models of 'raft' domains in biological membrane...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1045
更新日期:2012-09-01 00:00:00
abstract::Cell polarity is the asymmetric compartmentalization of cellular components. An opposing gradient of partitioning-defective protein kinases, atypical protein kinase C (aPKC) and PAR-1, at the cell cortex guides diverse asymmetries in the structure of metazoan cells, but the mechanism underlying their spatial patternin...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/s41589-018-0117-1
更新日期:2018-10-01 00:00:00
abstract::Cell-permeable small molecules that inhibit their targets on fast timescales are powerful probes of cell-division mechanisms. Such inhibitors have been identified using phenotype-based screens with chemical libraries. However, the characteristics of compound libraries needed to effectively span cell-division phenotype...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio826
更新日期:2006-11-01 00:00:00
abstract::Actin filament dynamics are critical in cell motility. The structure of actin filament changes spontaneously and can also be regulated by actin-binding proteins, allowing actin to readily function in response to external stimuli. The interaction with the motor protein myosin changes the dynamic nature of actin filamen...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio763
更新日期:2006-02-01 00:00:00
abstract::Intracellular Ca(2+) regulates numerous proteins and cellular functions and can vary substantially over submicron and submillisecond scales, so precisely localized fast detection is desirable. We have created a approximately 1-kDa biarsenical Ca(2+) indicator, called Calcium Green FlAsH (CaGF, 1), to probe [Ca(2+)] su...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.2007.4
更新日期:2007-07-01 00:00:00
abstract::The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.926
更新日期:2012-04-01 00:00:00
abstract::We identify an Arabidopsis pyridoxal-phosphate-dependent aminotransferase, VAS1, whose loss-of-function simultaneously increases amounts of the phytohormone auxin and the ethylene precursor 1-aminocyclopropane-1-carboxylate. VAS1 uses the ethylene biosynthetic intermediate methionine as an amino donor and the auxin bi...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1178
更新日期:2013-04-01 00:00:00
abstract::Nitrite represents a bioactive reservoir of nitric oxide (NO) that may modulate vasodilation, respiration and cytoprotection after ischemia-reperfusion injury. Although nitrite formation is thought to occur via reaction of NO with oxygen, this third-order reaction cannot compete kinetically with the reaction of NO wit...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio813
更新日期:2006-09-01 00:00:00
abstract::Changes in the cellular environment modulate protein energy landscapes to drive important biology, with consequences for signaling, allostery and other vital processes. The effects of ubiquitination are particularly important because of their potential influence on degradation by the 26S proteasome. Moreover, proteaso...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/s41589-020-0556-3
更新日期:2020-08-01 00:00:00
abstract::Mammals that degrade uric acid are not affected by gout or urate kidney stones. It is not fully understood how they convert uric acid into the much more soluble allantoin. Until recently, it had long been thought that urate oxidase was the only enzyme responsible for this conversion. However, detailed studies of the m...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio768
更新日期:2006-03-01 00:00:00
abstract::Biotin is an essential vitamin in plants and mammals, functioning as the carbon dioxide carrier within central lipid metabolism. Bacterial pimeloyl-CoA synthetase (BioW) acts as a highly specific substrate-selection gate, ensuring the integrity of the carbon chain in biotin synthesis. BioW catalyzes the condensation o...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.2361
更新日期:2017-06-01 00:00:00
abstract::The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this kno...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1584
更新日期:2014-09-01 00:00:00
abstract::Benzylisoquinoline alkaloids (BIAs) are a diverse family of plant-specialized metabolites that include the pharmaceuticals codeine and morphine and their derivatives. Microbial synthesis of BIAs holds promise as an alternative to traditional crop-based manufacturing. Here we demonstrate the production of the key BIA i...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1816
更新日期:2015-07-01 00:00:00
abstract::Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Rather than focusing on therapeutics that target in vitro viability, much like conventional antibiotics, an alte...
journal_title:Nature chemical biology
pub_type: 杂志文章,评审
doi:10.1038/nchembio.2007.24
更新日期:2007-09-01 00:00:00
abstract::Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is tox...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.2070
更新日期:2016-06-01 00:00:00
abstract::The inability of cells to properly fold, modify and assemble secretory and transmembrane proteins leads to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Under these conditions of 'ER stress', cell survival depends on homeostatic benefits from an intracellular signaling pathway called the unfold...
journal_title:Nature chemical biology
pub_type: 杂志文章,评审
doi:10.1038/nchembio.1664
更新日期:2014-11-01 00:00:00
abstract::Concatenation of engineered biocatalysts into multistep pathways markedly increases their utility, but the development of generalizable assembly methods remains a major challenge. Herein we evaluate 'bioretrosynthesis', which is an application of the retrograde evolution hypothesis, for biosynthetic pathway constructi...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.1494
更新日期:2014-05-01 00:00:00
abstract::Foldamers are sequence-specific oligomers akin to peptides, proteins and oligonucleotides that fold into well-defined three-dimensional structures. They offer the chemical biologist a broad pallet of building blocks for the construction of molecules that test and extend our understanding of protein folding and functio...
journal_title:Nature chemical biology
pub_type: 杂志文章,评审
doi:10.1038/nchembio876
更新日期:2007-05-01 00:00:00
abstract::ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N6-propargyl adenosine (N6pA), is metabolically inco...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.2280
更新日期:2017-03-01 00:00:00
abstract::Methods to evolve synthetic, rather than biological, polymers could significantly expand the functional potential of polymers that emerge from in vitro evolution. Requirements for synthetic polymer evolution include (i) sequence-specific polymerization of synthetic building blocks on an amplifiable template, (ii) disp...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.280
更新日期:2010-02-01 00:00:00
abstract::The eukaryotic replicative DNA polymerases (Pol α, δ and ɛ) and the major DNA mutagenesis enzyme Pol ζ contain two conserved cysteine-rich metal-binding motifs (CysA and CysB) in the C-terminal domain (CTD) of their catalytic subunits. Here we demonstrate by in vivo and in vitro approaches the presence of an essential...
journal_title:Nature chemical biology
pub_type: 杂志文章
doi:10.1038/nchembio.721
更新日期:2011-11-27 00:00:00