Sequence elements that contribute to the degradation of yeast Gα

Schauber, Cherylene; Chen, Li; Tongaonkar, Prasad; Vega, Irving E.; Madura, Kiran

doi:10.1046/j.1365-2443.1998.00192.x

Cited by 19 publications

(15 citation statements)

References 43 publications

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“…Thus it can target N-␣-acetylated proteins (132) and also the yeast G␣ protein involved in growth regulation in response to pheromones (288,387). The Cup9 transcription factor is a negative regulator of the di/tripeptide transporter Ptr1 gene.…”

Section: Peptide Binding-mediated Allosteric Activation (Fig 3b)mentioning

confidence: 99%

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Glickman

Ciechanover

2002

Physiological Reviews

3,717

3,031

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Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, considered to be a nonspecific, dead-end process. Although it was known that proteins do turn over, the large extent and high specificity of the process, whereby distinct proteins have half-lives that range from a few minutes to several days, was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly change this view, because it became clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate specific. The discovery of the complex cascade of the ubiquitin pathway revolutionized the field. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease. With the multitude of substrates targeted and the myriad processes involved, it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases, certain malignancies, and neurodegeneration among them. Degradation of a protein via the ubiquitin/proteasome pathway involves two successive steps: 1) conjugation of multiple ubiquitin moieties to the substrate and 2) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation, and major key questions have remained unsolved. Among these are the modes of specific and timed recognition for the degradation of the many substrates and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases.

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Section: Peptide Binding-mediated Allosteric Activation (Fig 3b)mentioning

confidence: 99%

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Glickman

Ciechanover

2002

Physiological Reviews

3,717

3,031

View full text Add to dashboard Cite

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“…The known functions of the N-end rule pathway include the control of peptide import in S. cerevisiae, through the degradation of CUP9, a transcriptional repressor of the peptide transporter PTR2 (30) (this control includes a positive feedback mediated by the type 1 and type 2 sites of UBR1 (31)); the degradation of GPA1, one of two G␣ proteins in S. cerevisiae (32); and the degradation of alphaviral RNA polymerases and other viral proteins in infected metazoan cells (33,34). Physiological N-end rule substrates were also identified among the proteins secreted into the cytosol of the mammalian cell by intracellular parasites such as the bacterium Listeria monocytogenes (35).…”

mentioning

confidence: 99%

RGS4 Is Arginylated and Degraded by the N-end Rule Pathway in Vitro

Davydov

Varshavsky

2000

Journal of Biological Chemistry

143

147

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The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. We used an expression-cloning screen to search for mouse proteins that are degraded by the ubiquitin/proteasome-dependent N-end rule pathway in a reticulocyte lysate. One substrate thus identified was RGS4, a member of the RGS family of GTPase-activating proteins that downregulate specific G proteins. A determinant of the RGS4 degradation signal (degron) was located at the N terminus of RGS4, because converting cysteine 2 to either glycine, alanine, or valine completely stabilized RGS4. Radiochemical sequencing indicated that the N-terminal methionine of the lysate-produced RGS4 was replaced with arginine. Since N-terminal arginine is a destabilizing residue not encoded by RGS4 mRNA, we conclude that the degron of RGS4 is generated through the removal of N-terminal methionine and enzymatic arginylation of the resulting N-terminal cysteine. RGS16, another member of the RGS family, was also found to be an N-end rule substrate. RGS4 that was transiently expressed in mouse L cells was short-lived in these cells. However, the targeting of RGS4 for degradation in this in vivo setting involved primarily another degron, because N-terminal variants of RGS4 that were stable in reticulocyte lysate remained unstable in L cells.

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“…The type 2 site binds the bulky hydrophobic N-terminal terminal residues Phe, Leu, Trp, Tyr, and Ile (35,63). Ubr1p contains yet another substrate-binding site that targets proteins such as Cup9p and Gpa1p, which bear internal (non-N-terminal) degrons (12,54). The Ubr1 genes encoding mouse and human N-recognins, also called E3␣, have been cloned (36), and mouse strains lacking Ubr1 have recently been constructed (Y. T. Kwon and A. Varshavsky, unpublished data).…”

mentioning

confidence: 99%

“…The known functions of the N-end rule pathway include the control of peptide import in S. cerevisiae, through the degradation of Cup9p, a transcriptional repressor of PTR2, which encodes the peptide transporter (1, 12); a mechanistically undefined role in regulating the Sln1p-dependent phosphorylation cascade that mediates osmoregulation in S. cerevisiae (47); the degradation of alphaviral RNA polymerases and other viral proteins in infected metazoan cells (19,38); and the degradation of Gpa1p, a G␣ protein of S. cerevisiae (43,54). Physiological N-end rule substrates were also identified among the proteins secreted into the mammalian cell's cytosol by intracellular parasites such as the bacterium Listeria monocytogenes.…”

mentioning

confidence: 99%

Altered Activity, Social Behavior, and Spatial Memory in Mice Lacking the NTAN1p Amidase and the Asparagine Branch of the N-End Rule Pathway

Kwon

Balogh

Davydov

et al. 2000

Molecular and Cellular Biology

129

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The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3␣, the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (Nt N -amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1 ؊/؊ mouse strains lacked the Nt N -amidase activity but retained glutamine-specific Nt Q -amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1 ؊/؊ fibroblasts. The Ntan1 ؊/؊ mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains.

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Sequence elements that contribute to the degradation of yeast Gα

Cited by 19 publications

References 43 publications

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

RGS4 Is Arginylated and Degraded by the N-end Rule Pathway in Vitro

Altered Activity, Social Behavior, and Spatial Memory in Mice Lacking the NTAN1p Amidase and the Asparagine Branch of the N-End Rule Pathway

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