The N‐end rule pathway of protein degradation

Varshavsky, Alexander

doi:10.1046/j.1365-2443.1997.1020301.x

Cited by 316 publications

(252 citation statements)

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“…However, it is now appreciated that eukaryotic tRNAs serve additional functions in processes such as targeting proteins for degradation via the N-end rule pathway, signaling in the general amino acid control pathway, and regulation of apoptosis by binding cytochrome C (Varshavsky 1997;Dever and Hinnebusch 2005;Mei et al 2010). tRNAs are also employed as reverse transcription primers and for strand transfer during retroviral replication (Marquet et al 1995;Piekna-Przybylska et al 2010).…”

Section: Contents Continuedmentioning

confidence: 99%

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

2013

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Transfer RNAs (tRNAs) are essential for protein synthesis. In eukaryotes, tRNA biosynthesis employs a specialized RNA polymerase that generates initial transcripts that must be subsequently altered via a multitude of post-transcriptional steps before the tRNAs beome mature molecules that function in protein synthesis. Genetic, genomic, biochemical, and cell biological approaches possible in the powerful Saccharomyces cerevisiae system have led to exciting advances in our understandings of tRNA post-transcriptional processing as well as to novel insights into tRNA turnover and tRNA subcellular dynamics. tRNA processing steps include removal of transcribed leader and trailer sequences, addition of CCA to the 39 mature sequence and, for tRNA His , addition of a 59 G. About 20% of yeast tRNAs are encoded by intron-containing genes. The three-step splicing process to remove the introns surprisingly occurs in the cytoplasm in yeast and each of the splicing enzymes appears to moonlight in functions in addition to tRNA splicing. There are 25 different nucleoside modifications that are added post-transcriptionally, creating tRNAs in which 15% of the residues are nucleosides other than A, G, U, or C. These modified nucleosides serve numerous important functions including tRNA discrimination, translation fidelity, and tRNA quality control. Mature tRNAs are very stable, but nevertheless yeast cells possess multiple pathways to degrade inappropriately processed or folded tRNAs. Mature tRNAs are also dynamic in cells, moving from the cytoplasm to the nucleus and back again to the cytoplasm; the mechanism and function of this retrograde process is poorly understood. Here, the state of knowledge for tRNA post-transcriptional processing, turnover, and subcellular dynamics is addressed, highlighting the questions that remain. TABLE OF CONTENTS Abstract 43Introduction 44

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Section: Contents Continuedmentioning

confidence: 99%

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae

2013

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“…29,35 For example, WW domains in the variable amino terminal extension of both yeast RSP5 and its mammalian homolog Nedd4 bind to the PPxY sequences of their cellular substrates, the yeast RNA polymerase II (Rpb1) and the human epithelial sodium channel, respectively. [36][37][38] Analogous to a specific interaction of E3α/UBR1 with its cognate E2 ligase UBC2, Hect E3s bind to a distinct set of E2s, such as yeast UBC4 and UBC5 or human UbcH5, UbcH7, and UbcH8 via a specific interaction with the Hect domain. 33,39-41 X-ray diffraction analysis of the crystal structure of the E6-AP Hect domain bound its cognate UbcH7 reveals the overall organization of this complex as well as the detailed structural determinants responsible for the E2-E3 specificity.…”

Section: E3s (Ubiquitin-protein Ligases)mentioning

confidence: 99%

The ubiquitin‐proteasome pathway and proteasome inhibitors

Myung

Kim

Crews

2001

Medicinal Research Reviews

402

252

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The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasomemediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.

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“…Sequence determinants at both the N-and C-termini of proteins can influence their rate of degradation [2][3][4]. Therefore, in some cases affinity tags might improve the yield of recombinant proteins by rendering them more resistant to intracellular proteolysis [5].…”

Section: Introductionmentioning

confidence: 99%